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Drug A is Antithymocyte immunoglobulin (rabbit). Drug B is Raltitrexed. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Raltitrexed. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Antithymocyte immunoglobulin (rabbit) is indicated for prevention of renal transplant rejection. Raltitrexed is indicated for the treatment of malignant neoplasm of colon and rectum. Antithymocyte immunoglobulin (rabbit) pharmacodynamics: Antithymocyte Globulin (ATG) is a concentrated anti-human T-lymphocyte immunoglobulin preparation derived from rabbits after immunization with a T-lympoblast cell line. ATG is an immunosuppressive product for the prevention and treatment of acute rejection following organ transplantation. ATG reduces the host immune response against tissue transplants or organ allografts. Raltitrexed pharmacodynamics: Raltitrexed belongs to a group of medicines known as antimetabolites. It is used to treat cancer of the colon and rectum. It may also be used to treat other kinds of cancer, as determined by your doctor. Raltitrexed blocks an enzyme needed by the cell to live. This interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by raltitrexed, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern. The mechanism of action of Antithymocyte immunoglobulin (rabbit) is that it Binds to multiple, T-cell specific antigens leading to T-lymphocyte cell death via complement mediated cytotoxicity or apoptosis. The mechanism of action of Raltitrexed is that it Raltitrexed is an antineoplastic Agents and folic acid antagonists. Raltitrexed inhibits thymidylate synthase (TS) leading to DNA fragmentation and cell death. It is transported into cells via a reduced folate carrier. Inside the cell Raltitrexed is extensively polyglutamated, which enhances thymidylate synthase inhibitory power and duration. Inhibition of this enzyme results in decreased synthesis of thymidine triphosphate which is required for DNA synthesis. Antithymocyte immunoglobulin (rabbit) absorption: T-cell depletion usually observed within 1 day after initiating therapy. Average 21. 5 and 87 mcg/mL 4–8 hours post-infusion after first and last IV doses, respectively, when given for 7–11 days. No absorption information is available for Raltitrexed. No volume of distribution information is available for Antithymocyte immunoglobulin (rabbit). No volume of distribution information is available for Raltitrexed. No protein binding information is available for Antithymocyte immunoglobulin (rabbit). Raltitrexed is >93% bound to plasma proteins. Antithymocyte immunoglobulin (rabbit) metabolism: Most likely removed by opsonization via the reticuloendothelial system when bound to T lymphocytes, or by human antimurine antibody production. Raltitrexed metabolism: Raltitrexed is transported into cells via a reduced folate carrier. Inside the cell it is extensively polyglutamated by the enzyme folyl polyglutamate synthetase to polyglutamate forms. Antithymocyte immunoglobulin (rabbit) is eliminated via No route of elimination available. Raltitrexed is eliminated via No route of elimination available. The half-life of Antithymocyte immunoglobulin (rabbit) is 2-3 days, may increase after multiple doses administration. The half-life of Raltitrexed is 198 hours. No clearance information is available for Antithymocyte immunoglobulin (rabbit). No clearance information is available for Raltitrexed. Antithymocyte immunoglobulin (rabbit) toxicity includes Not known whether ATG (rabbit) distributes into human milk; however, other immunoglobulins are distributed into human milk. Raltitrexed toxicity includes Side effects include pale skin, troubled breathing, unusual bleeding or bruising, unusual tiredness or weakness, black, tarry stools, chest pain, chills, cough, fever, painful or difficult urination, shortness of breath, sore throat, sores, ulcers, or white spots on lips or in mouth, swollen glands, increase in bowel movements, loose stools, soft stools. Brand names of Antithymocyte immunoglobulin (rabbit) include No brand names available. Brand names of Raltitrexed include Tomudex. No synonyms are available for Antithymocyte immunoglobulin (rabbit). No synonyms are available for Raltitrexed. Antithymocyte immunoglobulin (rabbit) summary: It is Antithymocyte immunoglobulin (rabbit) is a purified form of rabbit anti-thymocyte antibodies used for immunosuppression in patients receiving kidney transplants. Raltitrexed summary: It is Raltitrexed is a folate analog thymidylate synthase inhibitor used in the treatment of advanced colorectal cancer. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Antithymocyte immunoglobulin (rabbit)

Drug A is Brompheniramine. Drug B is Vorinostat. The severity of the interaction is minor. The risk or severity of QTc prolongation can be increased when Brompheniramine is combined with Vorinostat. Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. Brompheniramine is indicated for the treatment of the symptoms of the common cold and allergic rhinitis, such as runny nose, itchy eyes, watery eyes, and sneezing. Vorinostat is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. Brompheniramine pharmacodynamics: Brompheniramine is an antihistaminergic medication of the propylamine class. It is a first-generation antihistamine. In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Brompheniramine is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. Vorinostat pharmacodynamics: No pharmacodynamics available. The mechanism of action of Brompheniramine is that it Brompheniramine is an antagonist of the H1 histamine receptors with moderate antimuscarinic actions, as with other common antihistamines such as diphenhydramine. Due to its anticholindergic effects, brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate. The mechanism of action of Vorinostat is that it Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC 50 < 86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of histones proteins. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. By inhibiting histone deacetylase, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized. Brompheniramine absorption: Antihistamines are well absorbed from the gastrointestinal tract after oral administration. No absorption information is available for Vorinostat. No volume of distribution information is available for Brompheniramine. No volume of distribution information is available for Vorinostat. No protein binding information is available for Brompheniramine. Vorinostat is 71% bound to plasma proteins. Brompheniramine metabolism: Hepatic (cytochrome P-450 system), some renal. Vorinostat metabolism: The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively. In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). Brompheniramine is eliminated via No route of elimination available. Vorinostat is eliminated via In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. However, renal excretion does not play a role in the elimination of vorinostat. The half-life of Brompheniramine is No half-life available. The half-life of Vorinostat is 2 hours. No clearance information is available for Brompheniramine. No clearance information is available for Vorinostat. Brompheniramine toxicity includes Oral, rat: LD 50 = 318 mg/kg. Signs of overdose include fast or irregular heartbeat, mental or mood changes, tightness in the chest, and unusual tiredness or weakness. No toxicity information is available for Vorinostat. Brand names of Brompheniramine include Bromfed DM, Lodrane D, M-end PE, Mar-cof BP. Brand names of Vorinostat include Zolinza. No synonyms are available for Brompheniramine. Brompheniramin Bromphéniramine Brompheniramine Brompheniraminum No synonyms are available for Vorinostat. SAHA Suberanilohydroxamic acid Suberoylanilide hydroxamic acid Vorinostat Vorinostatum Brompheniramine summary: It is Brompheniramine is a histamine H1 antagonist used to treat coughs, upper respiratory symptoms, and nasal congestion associated with allergies and the common cold. Vorinostat summary: It is Vorinostat is a histone deacetylase (HDAC) inhibitor used for the treatment of cutaneous manifestations in patients with progressive, persistent, or recurrent cutaneous T- cell lymphoma (CTCL) following prior systemic therapies. Answer: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females.

Brompheniramine

Drug A is Bromazepam. Drug B is Dabigatran etexilate. The severity of the interaction is minor. Bromazepam may decrease the excretion rate of Dabigatran etexilate which could result in a higher serum level. The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes, they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. Bromazepam is indicated for the short-term treatment of insomnia, short-term treatment of anxiety or panic attacks, if a benzodiazepine is required, and the alleviation of the symptoms of alcohol- and opiate-withdrawal. Dabigatran etexilate is indicated for Dabigatran etexilate is available in both oral pellet and capsule form. Dabigatran etexilate pellets are indicated for the treatment of venous thromboembolic events (VTE) in pediatric patients between three months and 12 years of age who have been treated with a parenteral anticoagulant for at least 5 days. They are also indicated in the same age group to reduce the risk of recurrence of VTE in patients who have been previously treated. In capsule form, dabigatran etexilate is indicated in adults to reduce the risk of stroke and systemic embolism associated with non-valvular atrial fibrillation and for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days. It is also indicated in adults to reduce the risk of recurrence of DVT and PE in patients who have been previously treated and for the prophylaxis of DVT and PE in patients who have undergone hip replacement surgery. Lastly, it is indicated in pediatric patients between eight and 18 years of age for the treatment of venous thromboembolic events (VTE) in patients who have been treated with a parenteral anticoagulant for at least 5 days and to reduce the risk of recurrence of VTE in patients who have been previously treated. Dabigatran etexilate is also approved by the EMA to prevent VTE in adult patients. For pediatric patients, Dabigatran etexilate is used to treat TVE and prevent recurrent TVE for patients from birth to less than 18 years of age. Bromazepam pharmacodynamics: Bromazepam is a lipophilic, long-acting benzodiazepine and with sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties. It does not possess any antidepressant qualities. Bromazepam, like other benzodiazepines, presents a risk of abuse, misuse, and dependence. According to many psychiatric experts, Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. Dabigatran etexilate pharmacodynamics: Dabigatran etexilate is a double prodrug that is hydrolyzed to the active dabigatran by intestinal and hepatic carboxylesterases. Dabigatran is a reversible competitive thrombin inhibitor that directly inhibits the conversion by thrombin of fibrinogen to fibrin, impairing the clotting process and acting as an anticoagulant. Dabigatran use prolongs coagulation markers such as the activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), thrombin time (TT), and dilute thrombin time (dTT), but not the international normalized ratio (INR), which cannot be used in this context as it can in warfarin monitoring. As with all anticoagulant therapies, dabigatran carries a risk of bleeding, which may increase with concomitant use of antiplatelet agents, fibrinolytic therapy, heparins, or chronic NSAID use, and should be monitored for. Premature discontinuation of dabigatran, in the absence of an alternative anticoagulant, also carries an increased risk of thromboembolic events. Due to the risk of an epidural or spinal hematoma, dabigatran should generally not be used in the context of neuraxial anesthesia or spinal puncture; if such use is unavoidable, careful monitoring should be employed. Dabigatran should not be used in patients with prosthetic heart valves due to an increased occurrence of major bleeding and thromboembolic events. Dabigatran is a substrate of the P-gp transporter and should generally not be administered together with P-gp inhibitors or inducers, especially in patients with impaired renal function. Lastly, dabigatran or any other direct-acting oral anticoagulant should not be administered in patients with triple-positive antiphospholipid syndrome (APS) due to an increased risk of recurrent thrombotic events. In case of the need for emergency reversal, idarucizumab is available for use in adult patients; the safety and efficacy of idarucizumab has not been established in pediatric patients yet, for whom reversal may be achieved through hemodialysis, prothrombin complex concentrates, or recombinant FVIIa. However, none of these have been sufficiently evaluated in clinical trials. The mechanism of action of Bromazepam is that it Bromazepam binds to the GABA-A receptor producing a conformational change and potentiating its inhibitory effects. Other neurotransmitters are not influenced. The mechanism of action of Dabigatran etexilate is that it Hemostasis is a complex process that balances coagulation to prevent excessive thrombus formation or excessive bleeding. Central to the coagulation process is the serine protease thrombin (FIIa), which is synthesized as inactive prothrombin (FII) and subsequently activated by FXa/FVa, leading to a positive feedback loop and the production of large quantities of thrombin; once enough thrombin is formed, it cleaves soluble fibrinogen to form insoluble fibrin fibres that, together with aggregated platelets, form a clot. Although beneficial in wound healing, aberrant thrombus formation can lead to serious health consequences. Dabigatran is a univalent reversible direct thrombin inhibitor (DTI) that competitively inhibits thrombin with a K i of 4. 5 ± 0. 2 nmol/L. Furthermore, the reversible nature of the inhibition is believed to allow for some normal physiological thrombin function, which may help alleviate some adverse effects associated with anticoagulation therapy. In addition, dabigatran has several glucuronidated metabolites, all of which have been shown to possess in vitro activity similar to the parent compound. In addition to a direct effect on thrombin activity, dabigatran has also been shown to inhibit platelet aggregation, another step in the coagulation pathway. However, the mechanism remains unclear as dabigatran inhibits platelet aggregation stimulated by thrombin and von Willebrand factor (vWF), but not by other pathways such as ADP- or thromboxane A2-induced aggregation. Bromazepam absorption: Bioavailability is 84% following oral administration. The time to peak plasma level is 1 - 4 hours. Bromazepam is generally well absorbed after oral administration. Dabigatran etexilate absorption: Oral dabigatran has a bioavailability of 3-7%, although the relative bioavailability of dabigatran pellets is 37% higher than that for capsules and the bioavailability increases to 75% when the capsule shell is removed; dabigatran capsules should not be tampered with in any way prior to administration. The Cmax is achieved by one hour following oral dosing, which is extended to two hours if accompanied by a high-fat meal. Dabigatran can be taken with or without food. Dabigatran pharmacokinetics are approximately linear over a range of 10-400 mg in healthy adults and adult patients and it has an accumulation factor of two in adult and pediatric patients. The volume of distribution of Bromazepam is 1. 56 L/kg. The volume of distribution of Dabigatran etexilate is Dabigatran has a volume of distribution of 50-70L. Bromazepam is 70% bound to plasma proteins. Dabigatran etexilate is Dabigatran is ~35% bound to plasma proteins, including human serum albumin. bound to plasma proteins. Bromazepam metabolism: Hepatically, via oxidative pathways (via an enzyme belonging to the Cytochrome P450 family of enzymes). One of the main metabolites is 3-hydroxybromazepam. It is pharmacologically active and the half life is similar to that of the parent compound. Dabigatran etexilate metabolism: Dabigatran is administered as the orally available prodrug dabigatran etexilate that is subsequently metabolized to the active form. In vitro studies and observations regarding the oral bioavailability and levels of plasma prodrug suggest extensive first-pass metabolism by carboxylesterases, first by intestinal CES2 to form BIBR0951 (also known as M2) and then subsequently by hepatic CES1 to form dabigatran. Dabigatran etexilate can also first undergo CES1-mediated hydrolysis to BIBR1087 (M1) followed by CES2-mediated hydrolysis to dabigatran, though it is hypothesized that the former pathway accounts for most of the active form in plasma. Dabigatran can undergo 1- O -acyl glucuronidation by UGT1A9, UGT2B7, and UGT2B15 followed by acyl migration to form the corresponding 2- O -, 3- O -, and 4- O -acyl glucuronides; all of these acyl glucuronides exhibit activity similar to dabigatran but account for a small fraction of recovered metabolites. In addition to these better characterized metabolic pathways, detailed LC/MS characterization suggests a wide variety of possible metabolites following oral or intravenous administration, most of which are present in only trace amounts in plasma, urine, or feces. These include a variety of oxidation, hydrolysis, and conjugation products, including through the addition of mannitol. Bromazepam is eliminated via Urine (69%), as metabolites. Dabigatran etexilate is eliminated via Dabigatran is primarily eliminated in the urine. Following oral administration of radiolabeled dabigatran, 7% of the radioactivity is recovered in urine and 86% is recovered in feces. The half-life of Bromazepam is 10-20 hours. The half-life of Dabigatran etexilate is Dabigatran has a half-life of 12-17 hours in adult patients and 12-14 hours in pediatric patients. The clearance of Bromazepam is 0. 82 mL/min/kg. The clearance of Dabigatran etexilate is Following intravenous administration, renal clearance constitutes ~80% of total dabigatran clearance. No toxicity information is available for Bromazepam. Dabigatran etexilate toxicity includes No human studies involving pregnancy, labor and delivery, nursing, or pediatrics. Geriatric patients are at higher risk of adverse effects than younger patients but the risk to benefit ratio is generally still favourable for older patients. Patients with a creatinine clearance of 15-30mL/min should have their doses of dabigatran etexilate reduced, and no data is available for patients with a creatinine clearance below 15mL/min. In animal studies, dabigatran increases the rates of dead offspring and causes uterine and vaginal bleeding close to birth. Dabigatran may or may not be excreted in breast milk so the risk and benefit of stopping the drug or stopping breast feeding must be considered. Brand names of Bromazepam include No brand names available. Brand names of Dabigatran etexilate include Pradaxa. No synonyms are available for Bromazepam. No synonyms are available for Dabigatran etexilate. Bromazepam summary: It is Bromazepam is a short-acting benzodiazepine with intermediate onset commonly used to treat panic disorders and severe anxiety. Dabigatran etexilate summary: It is Dabigatran etexilate is an anticoagulant used for the prevention of venous thromboembolic events or stroke in patients with recent elective hip or knee replacement surgery and atrial fibrillation. Answer: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

Bromazepam

Drug A is Bromazepam. Drug B is Riluzole. The severity of the interaction is moderate. The risk or severity of CNS depression can be increased when Riluzole is combined with Bromazepam. Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. Bromazepam is indicated for the short-term treatment of insomnia, short-term treatment of anxiety or panic attacks, if a benzodiazepine is required, and the alleviation of the symptoms of alcohol- and opiate-withdrawal. Riluzole is indicated for the treatment of amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease). Bromazepam pharmacodynamics: Bromazepam is a lipophilic, long-acting benzodiazepine and with sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties. It does not possess any antidepressant qualities. Bromazepam, like other benzodiazepines, presents a risk of abuse, misuse, and dependence. According to many psychiatric experts, Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. Riluzole pharmacodynamics: Riluzole, a member of the benzothiazole class, is indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS). Riluzole extends survival and/or time to tracheostomy. It is also neuroprotective in various in vivo experimental models of neuronal injury involving excitotoxic mechanisms. The etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are not known, although a number of hypotheses have been advanced. One hypothesis is that motor neurons, made vulnerable through either genetic predisposition or environmental factors, are injured by glutamate. In some cases of familial ALS the enzyme superoxide dismutase has been found to be defective. The mechanism of action of Bromazepam is that it Bromazepam binds to the GABA-A receptor producing a conformational change and potentiating its inhibitory effects. Other neurotransmitters are not influenced. The mechanism of action of Riluzole is that it The mode of action of riluzole is unknown. Its pharmacological properties include the following, some of which may be related to its effect: 1) an inhibitory effect on glutamate release (activation of glutamate reuptake), 2) inactivation of voltage-dependent sodium channels, and 3) ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors. Bromazepam absorption: Bioavailability is 84% following oral administration. The time to peak plasma level is 1 - 4 hours. Bromazepam is generally well absorbed after oral administration. Riluzole absorption: Riluzole is well-absorbed (approximately 90%), with average absolute oral bioavailability of about 60% (CV=30%). A high fat meal decreases absorption, reducing AUC by about 20% and peak blood levels by about 45%. The volume of distribution of Bromazepam is 1. 56 L/kg. No volume of distribution information is available for Riluzole. Bromazepam is 70% bound to plasma proteins. Riluzole is 96% bound to plasma proteins, mainly to albumin and lipoprotein over the clinical concentration range. bound to plasma proteins. Bromazepam metabolism: Hepatically, via oxidative pathways (via an enzyme belonging to the Cytochrome P450 family of enzymes). One of the main metabolites is 3-hydroxybromazepam. It is pharmacologically active and the half life is similar to that of the parent compound. Riluzole metabolism: Riluzole is extensively metabolized to six major and a number of minor metabolites, which have not all been identified to date. Metabolism is mostly hepatic, consisting of cytochrome P450–dependent hydroxylation and glucuronidation. CYP1A2 is the primary isozyme involved in N-hydroxylation; CYP2D6, CYP2C19, CYP3A4, and CYP2E1 are considered unlikely to contribute significantly to riluzole metabolism in humans. Bromazepam is eliminated via Urine (69%), as metabolites. Riluzole is eliminated via No route of elimination available. The half-life of Bromazepam is 10-20 hours. The half-life of Riluzole is The mean elimination half-life of riluzole is 12 hours (CV=35%) after repeated doses. The clearance of Bromazepam is 0. 82 mL/min/kg. No clearance information is available for Riluzole. No toxicity information is available for Bromazepam. No toxicity information is available for Riluzole. Brand names of Bromazepam include No brand names available. Brand names of Riluzole include Exservan, Rilutek, Tiglutik. No synonyms are available for Bromazepam. No synonyms are available for Riluzole. Bromazepam summary: It is Bromazepam is a short-acting benzodiazepine with intermediate onset commonly used to treat panic disorders and severe anxiety. Riluzole summary: It is Riluzole is a glutamate antagonist used to treat amyotrophic lateral sclerosis. Answer: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

Bromazepam

Drug A is Pembrolizumab. Drug B is Dupilumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Pembrolizumab is combined with Dupilumab. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Pembrolizumab is indicated for Pembrolizumab is indicated for the following conditions: Melanoma for the treatment of patients with unresectable or metastatic melanoma (adult patients in the US and patients ≥12 years old in the EU) for the adjuvant treatment of adult and pediatric patients 12 years of age and older with Stage IIB, IIC, or III melanoma following complete resection Non-Small Cell Lung Cancer (NSCLC) in combination with pemetrexed and platinum-based chemotherapy as a first-line treatment for patients with metastatic nonsquamous NSCLC with no EGFR or ALK mutations in combination with carboplatin and paclitaxel as a first-line treatment for patients with metastatic squamous NSCLC as a monotherapy for the first-line treatment of NSCLC expressing PD-L1 with no EGFR or ALK mutations in patients with metastatic disease or stage III disease who are not candidates for surgery or chemoradiation as a monotherapy for the treatment of NSCLC expressing PD-L1 with disease progression on or after platinum-based chemotherapy - this includes patients with EGFR or ALK mutations, providing they have experienced disease progression on prior FDA-approved therapy for these aberrations in combination with platinum-based chemotherapy for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery Head and Neck Squamous Cell Cancer (HNSCC) in combination with fluorouracil and platinum-based chemotherapy as a first-line treatment for patients with metastatic or recurrent, unresectable HNSCC as a monotherapy for the first-line treatment of patients with metastatic or recurrent, unresectable HNSCC expressing PD-L1 as a monotherapy for the treatment of patients with metastatic or recurrent HNSCC with disease progression on or after platinum-based chemotherapy Classical Hodgkin Lymphoma (cHL) for the treatment of adult patients with relapsed or refractory cHL for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed following ≥2 lines of therapy Primary Mediastinal Large B-cell Lymphoma (PMBCL) for the treatment of adult and pediatric patients with refractory PMBCL, or PMBCL that has relapsed following ≥2 lines of therapy Urothelial Carcinoma for the treatment of locally advanced or metastatic urothelial carcinoma in patients ineligible for platinum-based chemotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-based chemotherapy or within 12 months of adjuvant/neoadjuvant platinum-based chemotherapy for the treatment of BCG vaccine -unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ, with or without papillary tumors, who are not candidates for cystectomy for the treatment of locally advanced or metastatic urothelial carcinoma in combination with enfortumab vedotin in adult patients ineligible for platinum-based chemotherapy under the accelerated approval from the FDA Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient Cancer (dMMR) as a last-line therapy for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer Gastric Cancer in combination with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy, as a first-line treatment for patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD -L1 (CPS ≥1) as determined by an FDA-approved test in combination with fluoropyrimidine - and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma Esophageal Cancer in combination with fluoropyrimidine- and platinum-based chemotherapy for the treatment of patients with locally advanced or metastatic esophageal or GEJ carcinoma who are not candidates for surgery or definitive chemoradiation as a monotherapy for the treatment of locally advanced or metastatic esophageal or GEJ carcinoma expressing PD-L1 in patients who are not candidates for surgery or definitive chemoradiation Cervical Cancer in combination with other chemotherapies, with or without bevacizumab, for the treatment of persistent, recurrent, or metastatic cervical cancer expressing PD-L1 as a monotherapy for the treatment of recurrent or metastatic cervical cancer expressing PD-L1 in patients who have experienced disease progression on or after previous chemotherapy in combination with chemoradiotherapy for the treatment of patients with FIGO 2014 Stage III -IVA cervical cancer Hepatocellular Carcinoma (HCC) as a monotherapy for the treatment of HCC in patients who have been previously treated with sorafenib Biliary Tract Cancer (BTC) in combination with gemcitabine and cisplatin for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer Merkel Cell Carcinoma (MCC) for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic MCC Renal Cell Carcinoma (RCC) in combination with either axitinib or lenvatinib as a first-line treatment for adult patients with advanced RCC for the adjuvant treatment of patients with RCC who are at an intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions Endometrial Carcinoma in combination with lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR who experience disease progression following prior systemic therapy and who are not candidates for surgery or radiation therapy as a monotherapy for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation Tumor Mutational Burden-High (TMB-H) Cancer as a last-line therapy for the treatment of adult and pediatric patients with unresectable or metastatic TMB-H solid tumors that have progressed following prior treatment Cutaneous Squamous Cell Carcinoma (cSCC) for the treatment of patients with recurrent or metastatic sCC, or locally advanced sCC that is not curable with surgery or radiation therapy Triple-Negative Breast Cancer (TNBC) for the treatment of patients with high-risk early-stage TNBC, in combination with chemotherapy as a neoadjuvant treatment followed by continued use as a single adjuvant agent following surgery in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic TNBC expressing PD-L1 For all approved adult indications, pembrolizumab may be used for an additional 6 weeks at 400mg weekly. Dupilumab is indicated for In the US, dupilumab is indicated for the treatment of patients aged six months and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. In Europe and Canada, the drug for this indication is approved for patients aged six years and older. In Europe, patients six to 11 years of age should have severe atopic dermatitis and be candidates for systemic therapy. Dupilumab can be used with or without topical corticosteroids for this condition. Dupilumab is indicated as an add-on maintenance treatment of patients aged six years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma. However, the drug is not indicated for relief of acute bronchospasm or status asthmaticus. Dupilumab is indicated as an add-on maintenance treatment in adult patients with inadequately controlled chronic rhinosinusitis with nasal polyposis. In Canada and Europe, it is used with intranasal corticosteroids. In the US and Europe, dupilumab is also indicated for the treatment of adults and children aged 12 years and older weighing at least 40 kg with eosinophilic esophagitis (EoE), and adults with prurigo nodularis. Pembrolizumab pharmacodynamics: Pembrolizumab exerts its pharmacologic effects by releasing PD-1 pathway-mediated inhibition of the immune response, which in turn improves the anti-tumor immune response. Due to its relatively broad mechanism of action, it is useful in the treatment of a wide variety of cancers. Pembrolizumab can cause immune-mediated adverse reactions - including hepatitis, nephritis, and pneumonitis - in any organ system or tissue. Careful monitoring of the patient (including laboratory evaluation of liver, kidney, and thyroid function) should occur at baseline and periodically throughout therapy to monitor for emerging immune-mediated reactions. Dupilumab pharmacodynamics: Dupilumab is an recombinant human IgG4 antibody to the IL-4 receptor that works by inhibiting the activation of certain pro-inflammatory cytokines that are implicated in the pathophysiology of several allergic and atopic conditions, including asthma, chronic rhinosinusitis with nasal polyps, and food and environmental allergies. In vivo, dupilumab was shown to reduce the levels of type 2 inflammatory biomarkers associated with atopic dermatitis, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE, allergen-specific IgE, and lactate dehydrogenase (LDH). A decrease in the levels of biomarkers of asthma, such as FeNO, eotaxin-3, IgE, periostin, and eotaxin-3 (CCL26) was also observed. Since dupilumab works to suppress the immune response, it is proposed that it may influence the immune response against some infections, such as helminth infections, by inhibiting IL-4/IL-13 signaling. It is advised that infections are appropriately treated until resolved before initiating dupilumab therapy. While findings of some in vitro and in vivo studies suggest that some cytokine modulators may influence the expression and activity of specific cytochrome P450 (CYP450) enzymes, an open-label drug-drug interaction study demonstrated that dupilumab displays no significant effect on the activity of CYP450 enzymes studied (CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6). The mechanism of action of Pembrolizumab is that it Pembrolizumab binds with high affinity to the cell surface receptor programmed cell death protein 1 (PD-1) and antagonizes its interaction with its known ligands PD-L1 and PD-L2. Under normal circumstances, the binding of the ligands of PD-1 to the receptor inhibits the TCR-mediated T-cell proliferation and cytokine production. This inhibitory signal appears to play a role in self-tolerance and collateral damage minimization after immune responses against a pathogen and maternal tolerance to fetal tissue. The binding of pembrolizumab to PD-1 prevents this inhibitory pathway, causing a physiological shift towards immune reactivity and enhancing tumor immunosurveillance and anti-tumor immune response. The mechanism of action of Dupilumab is that it Type 2 inflammatory processes in various allergic and atopic conditions, such as asthma and atopic diseases, involve the type 2 helper T-cell (Th2) immunity. Upregulation of this Type 2/Th2 pathway is commonly observed in other inflammatory conditions and the activation of Th2 cells is linked to the production of Th2-associated cytokines, such as interleukin (IL) 4, IL-5, IL-9, and IL-13. IL-4 and IL-13 play a central role in inducing inflammatory conditions such as allergic rhinitis, asthma, and atopic dermatitis, by regulating Type 2 inflammation and immune function. These inflammatory cytokines work by modulating gene expression downstream of receptor signalling, regulating Th2 cell differentiation, and activating inflammatory cells such as mast cells and macrophages. There are two types of receptors for IL-4: the type 1 receptor, which is composed of the IL-4 chain (IL-4Rα) and a γ chain (γC), and the type 2 receptor, which is composed of the IL-4Rα chain and the α1 chain of the IL-13 receptor (IL-13Rα1). Essentially, IL‐4Rα is a component shared by the IL‐4 and IL-13 receptor complexes and is ubiquitously expressed on both innate and adaptive immune cells to promote the signaling of IL-4 and IL-13. The type I receptor is primarily expressed on lymphocytes and controls Th2-cell differentiation, whereas the type II receptor is mostly found across resident and myeloid cells. Dupilumab is a fully human monoclonal antibody directed against IL‐4Rα to inhibit the signalling of IL‐4 and IL‐13. Dupilumab inhibits IL-4 signalling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα). It ultimately downregulates type-2 immunity. Pembrolizumab absorption: Intravenously administered pembrolizumab is completely bioavailable. Steady-state is reached after approximately 16 weeks. Dupilumab absorption: The Cmax following administration of a single subcutaneous dose of 600 mg or 400 mg of dupilumab were 70. 1 ± 24. 1 mcg/mL or 41. 8 ± 12. 4 mcg/mL, respectively. The Tmax ranged from 3 to 7 days following administration of a single subcutaneous dose ranging from 75 to 600 mg. Following a subcutaneous dose, the absolute bioavailability of dupilumab ranged between 61% and 64% in patients with atopic dermatitis or asthma. In clinical trials, the steady-state concentrations were reached by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week. At these concentrations, the mean trough concentrations ranged from 60. 3 ± 35. 1 mcg/mL to 79. 9 ± 41. 4 mcg/mL for 300 mg dose and from 29. 2 ± 18. 7 to 36. 5 ± 22. 2 mcg/mL for 200 mg dose administered every other week. The volume of distribution of Pembrolizumab is The steady-state volume of distribution of pembrolizumab is approximately 6 liters. The volume of distribution of Dupilumab is The estimated volume of distribution is 4. 8 ± 1. 3 L. Pembrolizumab is Pembrolizumab is not expected to bind to plasma proteins. bound to plasma proteins. Dupilumab is There is limited data on the serum protein binding profile of dupilumab. bound to plasma proteins. Pembrolizumab metabolism: Pembrolizumab is catalyzed into smaller peptides and amino acids via general protein degradation. Dupilumab metabolism: Being a monoclonal antibody, dupilumab is not expected to undergo significant hepatic metabolism. While the metabolism of dupilumab has not been characterized, it is speculated that dupilumab undergoes nonspecific degradation into smaller peptides and amino acids, as often observed with endogenous IgG. Pembrolizumab is eliminated via No route of elimination available. Dupilumab is eliminated via Being a monoclonal antibody, dupilumab is not expected to undergo significant renal elimination. It is proposed that dupilumab is eliminated via parallel linear and nonlinear pathways. At higher concentrations, dupilumab is primarily cleared through a non-saturable proteolytic pathway. At lower concentrations, it undergoes a non-linear saturable IL-4R α target-mediated elimination. The half-life of Pembrolizumab is The terminal half-life of pembrolizumab is 22 days. The half-life of Dupilumab is There is limited human data on the half-life of dupilumab. In single-dose pharmacokinetic studies, the mean half-life of dupilumab following intravenous or subcutaneous administration ranged from 4. 8 to 7 days in rats and 11. 7 to 20. 5 days in cynomolgus monkeys. In these studies, the mean half-life was comparable was comparable following intravenous and subcutaneous administration. The clearance of Pembrolizumab is Clearance is moderately lower at steady-state (195 mL/day) than after the first dose (252 mL/day), although this decrease is not clinically significant. The clearance of Dupilumab is There is limited data on the clearance of dupilumab. Pembrolizumab toxicity includes There are no data regarding overdosage with pembrolizumab. Dupilumab toxicity includes There is limited data on the overdose of dupilumab. As there is no specific treatment for dupilumab, close monitoring of the patient with appropriate symptomatic treatment is advised in case of suspected overdosage. []. Brand names of Pembrolizumab include Keytruda. Brand names of Dupilumab include Dupixent. No synonyms are available for Pembrolizumab. No synonyms are available for Dupilumab. Pembrolizumab summary: It is Pembrolizumab is a PD-1 blocking antibody used to treat various types of cancer, including metastatic melanoma, non small-cell lung cancer, cervical cancer, head and neck cancer, and Hodgkin's lymphoma. Dupilumab summary: It is Dupilumab is a monoclonal antibody used to treat moderate to severe atopic dermatitis, asthma, and nasal polyps accompanied by chronic rhinosinusitis in adolescents and adults. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Pembrolizumab

Drug A is Corticotropin. Drug B is Pefloxacin. The severity of the interaction is moderate. The risk or severity of tendinopathy can be increased when Corticotropin is combined with Pefloxacin. Fluoroquinolones are known to increase the risk of tendinitis and/or tendon rupture. 5,4,6 The risk of tendinopathy associated with fluoroquinolones, such as the affected drug, appears increased in patients taking concomitant oral corticosteroids, such as the subject drug. Other factors associated with fluoroquinolone-induced tendinopathy are old age, non-obesity, and female gender. Prescribing information also lists previous organ transplants, renal failure, physical activity, and previous tendon disorders. Tendinopathy can occur anywhere from hours to months after administration, occurs most commonly in the Achilles tendon (though it can occur in others), and may present bilaterally. Corticotropin is indicated for use as a diagnostic agent in the screening of patients presumed to have adrenocortical insufficiency. Purified corticotropin for injection is indicated for a variety of allergic and autoimmune conditions. Pefloxacin is indicated for the treatment of uncomplicated gonococcal urethritis in males and for gram-negative-bacterial infections in the gastrointestinal system and the genitourinary tract. Corticotropin pharmacodynamics: Corticotropin acts through the stimulation of cell surface ACTH receptors, which are primarily located on the adrenocortical cells. Corticotropin stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainly glucocorticoids but also sex steroids (androgens). Corticotropin is also related to the circadian rhythm in many organisms. Pefloxacin pharmacodynamics: Pefloxacin is a fluoroquinolone antibiotic. Flouroquinolones such as pefloxacin possess excellent activity against gram-negative aerobic bacteria such as E. coli and Neisseria gonorrhoea as well as gram-positive bacteria including S. pneumoniae and Staphylococcus aureus. They also posses effective activity against shigella, salmonella, campylobacter, gonococcal organisms, and multi drug resistant pseudomonas and enterobacter. The mechanism of action of Corticotropin is that it As a diagnostic aid (adrenocortical function), corticotropin combines with a specific receptor on the adrenal cell plasma membrane. In patients with normal adrenocortical function, it stimulates the initial reaction involved in the synthesis of adrenal steroids (including cortisol, cortisone, weak androgenic substances, and a limited quantity of aldosterone) from cholesterol by increasing the quantity of cholesterol within the mitochondria. Corticotropin does not significantly increase serum cortisol concentrations in patients with primary adrenocortical insufficiency (Addison's disease). The mechanism of action of corticotropin in the treatment of infantile myoclonic seizures is unknown. The mechanism of action of Pefloxacin is that it The bactericidal action of pefloxacin results from interference with the activity of the bacterial enzymes DNA gyrase and topoisomerase IV, which are needed for the transcription and replication of bacterial DNA. DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms. Interference with these two topoisomerases results in strand breakage of the bacterial chromosome, supercoiling, and resealing. As a result DNA replication and transcription is inhibited. Corticotropin absorption: Corticotropin is rapidly absorbed following intramuscular administration; the repository dosage form is slowly absorbed over approximately 8 to 16 hours. Pefloxacin absorption: Well absorbed by the oral route. No volume of distribution information is available for Corticotropin. No volume of distribution information is available for Pefloxacin. No protein binding information is available for Corticotropin. Pefloxacin is 20-30% bound to plasma proteins. No metabolism information is available for Corticotropin. Pefloxacin metabolism: Hepatic. Primary metabolites are pefloxacin N-oxide and norfloxacin. Corticotropin is eliminated via No route of elimination available. Pefloxacin is eliminated via No route of elimination available. The half-life of Corticotropin is About 15 minutes following intravenous administration. The half-life of Pefloxacin is 8. 6 hours. No clearance information is available for Corticotropin. No clearance information is available for Pefloxacin. No toxicity information is available for Corticotropin. Pefloxacin toxicity includes Adverse reactions include peripheral neuropathy, nervousness, agitation, anxiety, and phototoxic events (rash, itching, burning) due to sunlight exposure. Brand names of Corticotropin include Acthar, Cortrophin. Brand names of Pefloxacin include No brand names available. No synonyms are available for Corticotropin. No synonyms are available for Pefloxacin. Corticotropin summary: It is Corticotropin is a diagnostic agent used in the screening of patients presumed to have adrenocortical insufficiency. Pefloxacin summary: It is Pefloxacin is an antibiotic used to treat a variety of bacterial infections. Answer: Fluoroquinolones are known to increase the risk of tendinitis and/or tendon rupture. 5,4,6 The risk of tendinopathy associated with fluoroquinolones, such as the affected drug, appears increased in patients taking concomitant oral corticosteroids, such as the subject drug. Other factors associated with fluoroquinolone-induced tendinopathy are old age, non-obesity, and female gender. Prescribing information also lists previous organ transplants, renal failure, physical activity, and previous tendon disorders. Tendinopathy can occur anywhere from hours to months after administration, occurs most commonly in the Achilles tendon (though it can occur in others), and may present bilaterally.

Corticotropin

Drug A is Caplacizumab. Drug B is Ranibizumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Ranibizumab is combined with Caplacizumab. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Caplacizumab is indicated for Capacizumab is approved for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP) in conjunction with plasma exchange and immunosuppression in patients 18 years or older. aTTP is a rare autoimmune condition presented by a disruption of blood clotting order which is translated into systemic microvascular thrombosis leading to profound thrombocytopenia, hemolytic anemia and organ ischemia. It is caused by the production of autoantibodies against ADAMTS-13 which is the protein in charge of cleaving the von-Wilebrand factor. The lack of this process produces the generation of ultra large von Wilebrand multimers that bind to platelets and form microthrombi and causing thromboembolic complications. Previously, capacizumab was under review for the prevention of thrombosis in high-risk patients with acute coronary syndrome undergoing percutaneous coronary intervention but this indication was withdrawn. Ranibizumab is indicated for Ranibizumab injection for intravitreal use is indicated to treat Neovascular (wet) Age-related Macular Degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization by the FDA. Ranibizumab injection for intravitreal use via ocular implant is used to treat Neovascular (wet) Age-related Macular Degeneration (AMD) in patients who have responded to at least two intravitreal injections of a VEGF inhibitor. In Canada, ranibizumab is approved to treat adult patients with neovascular (wet) age-related macular degeneration (AMD) and visual impairment due to diabetic macular edema, macular edema secondary to retinal vein occlusion, choroidal neovascularisation (CNV) secondary to pathologic myopia (PM), and choroidal neovascularisation (CNV) secondary to ocular conditions other than AMD or PM, including but not limited to angioid streaks, postinflammatory retinochoroidopathy, central serous chorioretinopathy or idiopathic chorioretinopathy. In Europe, ranibizumab is also approved for the treatment of similar ophthalmological conditions, including neovascular (wet) age-related macular degeneration (AMD), visual impairment due to diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), and visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO) or choroidal neovascularisation (CNV) for adults and retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 3+) or AP-ROP (aggressive posterior ROP) disease for preterm infants. Caplacizumab pharmacodynamics: In vitro studies have shown a caplacizumab-driven complete inhibition of platelet aggregation and in phase II clinical trials, it was shown to reduce the activity of the von Willebrand factor by 20% from treatment day 1 until treatment day 30. The level of von Willebrand factor in the plasma was also significantly reduced due to the clearance of the von Willebrand-caplacizumab complex. In phase III clinical trials, more than 50% of the tested individuals reached a platelet normal count. In these trials, it was observed as well a significant reduction in the incidence of aTTP as well as a significant reduction in the median time to response of about 39%. However, as caplacizumab does not target autoimmune response, relapses were observed after treatment discontinuation. The last clinical trial prior approval showed production of a platelet count of more than 150,000 per mcl after the cessation of plasma exchange therapy for 5 days as well as a reduction of patient recurrent thrombotic thrombocytopenic purpura and of disease-related death during treatment. Ranibizumab pharmacodynamics: Ranibizumab is a vascular endothelial growth factor (VEGF-A) inhibitor used to manage ocular diseases with abnormal angiogenesis. It inhibits the formation of new blood vessels or neovascularization. Ultimately, ranibizumab works to slow down the loss of vision and causes significant visual improvement in patients with ocular degenerative disorders, such as age-related macular degeneration. It can also reduce retinal thickness. As ranibizumab has one binding site for VEGF, two drug molecules bind to one VEGF dimer. Ranibizumab lacks the Fc region of an antibody, which may prevent the drug from causing intraocular inflammation following intravitreal injection. The mechanism of action of Caplacizumab is that it Caplacizumab acts by targetting the A1 domain of the ultra-large von Willebrand factor which in order inhibits the interaction with the glycoprotein Ib-IX-V receptor in the platelets. Caplacizumab binds to von Willebrand factor with an affinity of 8. 5 nM, thus it is very target specific. [5305] The blockage of the von Willebrand factor prevents the interaction between the von Willebrand factor and the platelets, hence, preventing platelet aggregation. The mechanism of action of Ranibizumab is that it The pathogenesis of neovascular eye diseases is not fully understood; however, vascular endothelial growth factor-A (VEGF-A) has been implicated in the development of clinical manifestations, such as choroidal neovascularization. Neovascularization is characterized by aberrated proliferation of abnormal vessels in the choroid capillary matrix. As a member of the VEGF family, VEGF-A is a key regulator of vascular permeability and angiogenesis; thus, it has been studied as a therapeutic target for the treatment of a wide array of neovascular eye diseases, including neovascular (wet) age-related macular degeneration (AMD) and diabetic retinopathy. For example, increased VEGF-A levels in the vitreous were shown in patients with neovascular age-related macular degeneration. Ranibizumab is a recombinant humanized IgG1 kappa isotype monoclonal antibody directed against human VEGF-A. Ranibizumab binds to VEGF-A with high affinity as well as its biologically active forms, such as VEGF165, VEGF121, and VEGF110. Notably, VEGF165 is the most predominant isoform in the human eye that promotes ocular neovascularization. VEGF165 enhances vascular permeability, inhibits apoptosis, and causes endothelial-cell mobilization from the bone marrow and differentiation for angiogenesis. Ranibizumab binds to the receptor-binding site of VEGF-A, preventing it from binding to its receptors - VEGFR1 and VEGFR2 - that are expressed on the surface of endothelial cells. Ranibizumab thereby attenuates endothelial cell proliferation, vascular leakage, and new blood vessel formation. Caplacizumab absorption: After intravenous administration of caplacizumab, the pharmacokinetic profile is non-linear and to follow a non-compartmental model as the pharmacokinetic profile of this drug is dependent on the expression of von Willebrand factor. After administration, caplacizumab is rapidly absorbed with a dose-dependent behavior. The peak concentration was reached after 6-7 hours and it presents a very high bioavailability reaching approximately 90%. The subcutaneous administration of a dose of 10 mg of caplacizumab produced a peak concentration of 528 ng/ml and an AUC of 7951 ng. h/ml. Ranibizumab absorption: Ranibizumab rapidly penetrates through the retina to reach the choroid after intravitreal injection. Following monthly intravitreal administration of 0. 5 mg ranibizumab in patients with neovascular (wet) age-related macular degeneration, the mean Cmax (±SD) was 1. 7 (± 1. 1) ng/mL. Following an implant insertion, the mean (±SD) Cmax of ranibizumab was 0. 48 (±0. 17) ng/mL and median Tmax was 26 days, with a range of one to 89 days. The volume of distribution of Caplacizumab is The reported volume of distribution of caplacizumab is 6. 33 L. The volume of distribution of Ranibizumab is The apparent volume of the central compartment (Vd/F) is 2. 77 L. Ranibizumab is not shown to accumulate in serum. Due to its small size from lacking the Fc region of an antibody, ranibizumab achieves enhanced diffusion into the retina and choroid. Caplacizumab is This antibody acts directly on plasma proteins and thus, this parameter is not significant for drug description. bound to plasma proteins. Ranibizumab is There is no information available. bound to plasma proteins. Caplacizumab metabolism: Caplacizumab is degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. Ranibizumab metabolism: The metabolism of ranibizumab has not been studied. Since it is a monoclonal antibody fragment, ranibizumab is expected to undergo catabolism. Caplacizumab is eliminated via The elimination of caplacizumab is divided between target-driven disposition which is driven by the binding to the von Willebrand factor and non-target disposition driven by the combination of catabolism and renal elimination. Ranibizumab is eliminated via There is no information available. The half-life of Caplacizumab is The reported half-life is reported to be in the range of 16-27 hours. The half-life of Ranibizumab is The estimated average vitreous elimination half-life is approximately nine days following intravitreal injection. The half-life of ranibizumab implant is approximately 25 weeks. The clearance of Caplacizumab is As the elimination is highly divided among hepatic, target-driven and renal elimination, the calculation of the clearance rate is not significant for drug description. The clearance of Ranibizumab is In patients with retinal vein occlusion or diabetic macular edema, the apparent clearance (CL/F) of ranibizumab was 24. 8 L/day. Caplacizumab toxicity includes Cases of overdose are represented by an increased risk of bleeding and in these cases, external administration of von Willebrand factor concentrate should be done. To this point, there have not been performed studies regarding the effect on fertility, genotoxicity, or carcinogenicity. Ranibizumab toxicity includes There is no information available regarding the LD 50 values of ranibizumab. There is also limited clinical experience of ranibizumab overdose: concentrated doses as high as 2 mg ranibizumab in 0. 05 mL have been administered to patients, with no additional unexpected adverse reactions that were observed. Brand names of Caplacizumab include Cablivi. Brand names of Ranibizumab include Byooviz, Cimerli, Lucentis, Susvimo. No synonyms are available for Caplacizumab. No synonyms are available for Ranibizumab. Caplacizumab summary: It is Caplacizumab is a von Willebrand factor (vWF)-directed antibody fragment used to treat acquired thrombotic thrombocytopenic purpura (aTTP). Ranibizumab summary: It is Ranibizumab is a recombinant humanized monoclonal antibody and VEGF-A antagonist used for the management of macular edema after retinal vein occlusion, age-related macular degeneration (wet), and diabetic macular edema. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Caplacizumab

Drug A is Ofatumumab. Drug B is Ropivacaine. The severity of the interaction is moderate. The risk or severity of methemoglobinemia can be increased when Ofatumumab is combined with Ropivacaine. The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. Ofatumumab is indicated for Ofatumumab is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate. In patients with recurrent or progressive CLL, ofatumumab is indicated for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL. Ofatumumab is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab. Ofatumumab is also indicated for the treatment of adult patients with relapsing forms of multiple sclerosis, including active secondary progressive disease, clinically isolated syndrome, and relapsing-remitting disease. Ropivacaine is indicated for Ropivacaine is indicated in adult patients for the induction of regional or local anesthesia for surgery or acute pain management. Ofatumumab pharmacodynamics: Ofatumumab works by binding to and blocking the action of CD-20, a molecule expressed on the surface of both healthy and leukemic B lymphocytes. In patients with previously untreated chronic lymphocytic leukemia (CLL), ofatumumab caused B-cell depletion in the peripheral blood after six months following the last dose. However, observable depletion of B cells in the peripheral blood does not directly correlate with the depletion of B-cells in solid organs or malignant tumours. In vitro, ofatumumab induces complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Ropivacaine pharmacodynamics: In contrast to most other local anesthetics, the presence of epinephrine does not affect the time of onset, duration of action, or the systemic absorption of ropivacaine. The mechanism of action of Ofatumumab is that it CD20 is expressed on normal pre-B lymphocytes and mature B lymphocytes, as well as malignant B lymphocytes. Numerous studies demonstrate that the depletion of B-cells can significantly alleviate symptoms of many forms of leukemia and lymphoma, which are malignancies associated with B-cell dysfunctions and high expression of CD20. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small and large extracellular loops of the CD20 molecule. The Fab domain of ofatumumab binds to CD20, and this drug-target interaction does not result in immediate shedding and internalization of CD20 from the plasma membrane of B lymphocytes. This allows ofatumumab to persist on the B lymphocyte cell surface for an extended period and recruit immunological molecules or FcR-expressing innate effectors, such as macrophages, that mediate immune effector functions with strong cytotoxic effects. These immune effector functions include complement-dependent cytotoxicity (CCD) and antibody-dependent cellular cytotoxicity (ADCC), which promote the lysis of malignant B-cells. Complement-dependent cytotoxicity (CDC) involves translocation of the CD20 molecule into lipid rafts, which are involved in cell signalling and receptor trafficking. The mechanism by which ofatumumab exerts a therapeutic effect in multiple sclerosis patients is unknown but is presumed to still occur as a consequence of its ability to bind CD20. The mechanism of action of Ropivacaine is that it Local anesthetics like ropivacaine block the generation and conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. Specifically, they block the sodium channel and decrease chances of depolarization and consequent action potentials. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Ofatumumab absorption: In one study consisting of patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma, the Cmax was 94 μg/mL and the Tmax was 7. 3 hours following the first infusion of 300 mg ofatumumab. Following subcutaneous injection, ofatumumab is thought to be absorbed primarily into the lymphatic system. Subcutaneous dosing of 20 mg every four weeks resulted in a mean AUC tau of 483 μg*h/mL and a mean steady-state Cmax of 1. 43 μg/mL. Ropivacaine absorption: Ropivacaine pharmacokinetics are highly dependent on the dose, route of administration, and patient condition. Following epidural administration ropivacaine undergoes complete and biphasic absorption. The volume of distribution of Ofatumumab is In patients with CLL, the mean volume of distribution at steady-state was 5. 8 L. Repeated subcutaneous dosing with 20 mg of ofatumumab resulted in a steady-state volume of distribution of 5. 42 L. The volume of distribution of Ropivacaine is Following intravascular infusion, ropivacaine has a steady-state volume of distribution of 41 ± 7 liters. Ropivacaine is able to readily cross the placenta. Ofatumumab is There is limited information on the serum protein binding profile of ofatumumab. bound to plasma proteins. Ropivacaine is Ropivacaine is 94% protein-bound in plasma, primarily to α1-acid glycoprotein. bound to plasma proteins. Ofatumumab metabolism: Like other monoclonal antibodies, ofatumumab is expected to undergo lysosomal degradation by the reticuloendothelial system and protein catabolism by a target‐mediated disposition pathway. Ropivacaine metabolism: Ropivacaine undergoes extensive metabolism, primarily via CYP1A2-mediated aromatic hydroxylation to 3-OH-ropivacaine. The main metabolites excreted in the urine are the N-dealkylated metabolite (PPX) and 3-OH-ropivacaine. Other identified metabolites include 4-OH-ropivacaine, the 3-hydroxy-N-dealkylated (3-OH-PPX) and 4-hydroxy-N-dealkylated (4-OH-PPX) metabolites, and 2-hydroxy-methyl-ropivacaine (which has been identified but not quantified). Unbound PPX, 3-hydroxy-, and 4-hydroxy-ropivacaine have demonstrated pharmacological activity in animal models less than that of ropivacaine. Ofatumumab is eliminated via Ofatumumab undergoes elimination by a target-independent route and a target (B cell)-mediated route, with a dose-dependent clearance in the dose range of 100 to 2000 mg. As ofatumumab causes B-cell depletion, the clearance of ofatumumab mediated by B-cells is decreased substantially after subsequent drug infusions. Ropivacaine is eliminated via Following intravenous administration, 86% of the administered dose of ropivacaine is excreted in the urine, 1% of which comprises unchanged parent drug. The half-life of Ofatumumab is In patients with CLL, the mean half-life at steady state was 17. 1 days. Similarly, in patients given ofatumumab subcutaneously, the steady-state elimination half-life was estimated at 16 days. The half-life of Ropivacaine is The mean terminal half-life of ropivacaine is 1. 8 ± 0. 7 hours after intravascular administration and 4. 2 ± 1 hour after epidural administration. The clearance of Ofatumumab is In patients with CLL, the mean clearance at steady-state was 11. 6 mL/hour. In patients administered ofatumumab subcutaneously in repeated 20 mg injections, the steady-state clearance following B-cell depletion was estimated to be 0. 34 L/day. The clearance of Ropivacaine is Following intravenous administration, ropivacaine has a mean plasma clearance of 387 ± 107 mL/min, an unbound plasma clearance of 7. 2 ± 1. 6 L/min, and a renal clearance of 1 mL/min. Ofatumumab toxicity includes There is limited information on overdose of ofatumumab. Ofatumumab may cause B-cell depletion in the fetus when administered in pregnant women. Ropivacaine toxicity includes High systemic doses of ropivacaine can result in central nervous system (CNS) and cardiovascular effects, with the CNS effects usually occurring at lower blood plasma concentrations and additional cardiovascular effects occurring at higher concentrations (although cardiovascular collapse may occur at lower concentrations). CNS effects include CNS excitation involving nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, and seizures. CNS depressant effects may follow, associated with drowsiness, loss of consciousness, respiratory depression and apnea. Cardiovascular events may be caused by hypoxemia secondary to respiratory depression and include hypotension, bradycardia, arrhythmias, and/or cardiac arrest. Brand names of Ofatumumab include Arzerra, Kesimpta. Brand names of Ropivacaine include Naropin. No synonyms are available for Ofatumumab. No synonyms are available for Ropivacaine. Ropivacaina Ropivacaine Ropivacainum Ofatumumab summary: It is Ofatumumab is an anti-CD20 antibody used for the treatment of chronic lymphocytic leukemia (CLL) in selected patients with certain treatment histories and responsiveness to anticancer medications. Ropivacaine summary: It is Ropivacaine is an amide-type local anesthetic used for local or regional anesthesia during surgery and for short-term management of acute pain. Answer: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia.

Ofatumumab

Drug A is Bromocriptine. Drug B is Carvedilol. The severity of the interaction is moderate. The therapeutic efficacy of Bromocriptine can be increased when used in combination with Carvedilol. Diabetic patients taking beta blockers are 1. 27 times more likely to develop hypoglycemia than those not taking beta blockers. 1 Bromocriptine is indicated for the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor complications. Bromocriptine has also been used off-label to treat restless legs syndrome and neuroleptic malignant syndrome. Carvedilol is indicated for Carvedilol is indicated to treat mild to severe heart failure, left ventricular dysfunction after myocardial infarction with ventricular ejection fraction ≤40%, or hypertension. Bromocriptine pharmacodynamics: Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D 2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D 2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 -receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT) 1D, dopamine D 3, 5-HT 1A, 5-HT 2A, 5-HT 1B, and 5-HT 2C receptors, antagonist activity on α 2A -adrenergic, α 2C, α 2B, and dopamine D 1 receptors, partial agonist activity at receptor 5-HT 2B, and inactivates dopamine D 4 and 5-HT 7 receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e. g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT 1B and 5-HT 2B receptors. Carvedilol pharmacodynamics: Carvedilol reduces tachycardia through beta adrenergic antagonism and lowers blood pressure through alpha-1 adrenergic antagonism. It has a long duration of action as it is generally taken once daily and has a broad therapeutic index as patients generally take 10-80mg daily. Patients taking carvedilol should not abruptly stop taking this medication as this may exacerbate coronary artery disease. The mechanism of action of Bromocriptine is that it The dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. The mechanism of action of Carvedilol is that it Carvedilol inhibits exercise induce tachycardia through its inhibition of beta adrenoceptors. Carvedilol's action on alpha-1 adrenergic receptors relaxes smooth muscle in vasculature, leading to reduced peripheral vascular resistance and an overall reduction in blood pressure. At higher doses, calcium channel blocking and antioxidant activity can also be seen. The antioxidant activity of carvedilol prevents oxidation of low density lipoprotein and its uptake into coronary circulation. Bromocriptine absorption: Approximately 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1. 5 hours. Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours. Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2. 5 mg and decreased growth hormone concentrations persist for at least 4-5 hours. Carvedilol absorption: Carvedilol has a bioavailability of 25-35%. Carvedilol has a Tmax of 1 to 2 hours. Taking carvedilol with a meal increases Tmax without increasing AUC. Carvedilol doses of 50mg lead to a Cmax of 122-262µg/L and an AUC of 717-1600µg/L*h. Carvedilol doses of 25mg lead to a Cmax of 24-151µg/L and an AUC of 272-947µg/L*h. Carvedilol doses of 12. 5mg lead to a Cmax of 58-69µg/L and an AUC of 208-225µg/L*h. No volume of distribution information is available for Bromocriptine. The volume of distribution of Carvedilol is Carvedilol has a volume of distribution of 1. 5-2L/kg or 115L. Bromocriptine is 90-96% bound to serum albumin bound to plasma proteins. Carvedilol is Carvedilol is 98% protein bound in plasma. 95% of carvedilol is bound to serum albumin. bound to plasma proteins. Bromocriptine metabolism: Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion. Carvedilol metabolism: Carvedilol can be hydroxlated at the 1 position by CYP2D6, CYP1A2, or CYP1A1 to form 1-hydroxypheylcarvedilol; at the 4 position by CYP2D6, CYP2E1, CYP2C9, or CYP3A4 to form 4'-hydroxyphenylcarvedilol; at the 5 position by CYP2D6, CYP2C9, or CYP3A4 to form 5'-hydroxyphenylcarvedilol; and at the 8 position by CYP1A2, CYP3A4, and CYP1A1 to form 8-hydroxycarbazolylcarvedilol. Carvedilol can also be demethylated by CYP2C9, CYP2D6, CYP1A2, or CYP2E1 to form O-desmethylcarvedilol. Carvedilol and its metabolites may undergo further sulfate conjugation or glucuronidation before elimination. Carvedilol can be O-glucuronidated by UGT1A1, UGT2B4, and UGT2B7 to form carvedilol glucuronide. Bromocriptine is eliminated via Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. Carvedilol is eliminated via 16% of carvedilol is excreted in the urine with <2% excreted as unmetabolized drug. Carvedilol is primarily excreted in the bile and feces. The half-life of Bromocriptine is 2-8 hours. The half-life of Carvedilol is The half life of carvedilol is between 7-10 hours, though significantly shorter half lives have also been reported. No clearance information is available for Bromocriptine. The clearance of Carvedilol is The plasma clearance of carvedilol has been reported as 0. 52L/kg or 500-700mL/min. Bromocriptine toxicity includes Symptoms of overdosage include nausea, vomiting, and severe hypotension. The most common adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension. Carvedilol toxicity includes Patients experiencing an overdose may present with hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Patients should remain in a supine position and may be given atropine for bradycardia and glucagon followed by sympathomimetics to support cardiovascular function. Brand names of Bromocriptine include Cycloset, Parlodel. Brand names of Carvedilol include Coreg. No synonyms are available for Bromocriptine. Bromocriptine Bromocriptinum Bromocryptine Bromoergocriptine Bromoergocryptine No synonyms are available for Carvedilol. Carvédilol Carvedilolum Bromocriptine summary: It is Bromocriptine is a dopamine D2 receptor agonist used for the treatment of galactorrhea due to hyperprolactinemia and other prolactin-related conditions, as well as in early Parkinsonian Syndrome. Carvedilol summary: It is Carvedilol is a non selective beta-adrenergic antagonist used to treat mild to severe chronic heart failure, hypertension, and left ventricular dysfunction following myocardial infarction in clinically stable patients. Answer: Diabetic patients taking beta blockers are 1. 27 times more likely to develop hypoglycemia than those not taking beta blockers.

Bromocriptine

Drug A is Budesonide. Drug B is Pegcetacoplan. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Budesonide is combined with Pegcetacoplan. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Budesonide is indicated for Budesonide extended-release capsules are indicated for the treatment and maintenance of mild to moderate Crohn’s disease. Various inhaled budesonide products are indicated for prophylactic therapy in asthma and to reduce exacerbations of COPD. A budesonide nasal spray is available over the counter for symptoms of hay fever and upper respiratory allergies. Extended-release capsules are indicated to induce remission of mild to moderate ulcerative colitis and a rectal foam is used for mild to moderate distal ulcerative colitis. In addition, a delayed-release capsule formulation of budesonide is indicated to reduce proteinuria in adults with IgA nephropathy at risk of rapid disease progression. Budesonide is indicated to treat eosinophilic esophagitis (EoE): For this indication, it is only approved for use in adults in Europe while it is approved for short-term use (12 weeks) in patients 11 years of age and older in the US. Budesonide pharmacodynamics: Budesonide is a glucocorticoid used to treat respiratory and digestive conditions by reducing inflammation. It has a wide therapeutic index, as dosing varies highly from patient to patient. Patients should be counselled regarding the risk of hypercorticism and adrenal axis suppression. The mechanism of action of Budesonide is that it The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. Budesonide absorption: Extended release oral capsules are 9-21% bioavailable. A 9mg dose reaches a Cmax of 1. 50±0. 79ng/mL with a Tmax of 2-8h and an AUC of 7. 33ng*hr/mL. A high fat meal increases the Tmax by 2. 3h but otherwise does not affect the pharmacokinetics of budesonide. 180-360µg metered inhaled doses of budesonide are 34% deposited in the lungs, 39% bioavailable, and reach a Cmax of 0. 6-1. 6nmol/L with a Tmax of 10 minutes. A 1mg nebulized dose is 6% bioavailable, reaching a Cmax of 2. 6nmol/L with a Tmax of 20 minutes. A 9mg oral extended release tablet reaches a Cmax of 1. 35±0. 96ng/mL with a Tmax of 13. 3±5. 9h and an AUC of 16. 43±10. 52ng*hr/mL. Budesonide rectal foam 2mg twice daily has an AUC of 4. 31ng*hr/mL. The volume of distribution of Budesonide is The volume of distribution of budesonide is 2. 2-3. 9L/kg. Budesonide is Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. Budesonide is 85-90% protein bound in plasma. bound to plasma proteins. Budesonide metabolism: Budesonide is 80-90% metabolized at first pass. Budesonide is metabolized by CYP3A to its 2 major metabolites, 6beta-hydroxybudesonide and 16alpha-hydroxyprednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. CYP3A4 is the strongest metabolizer of budesonide, followed by CYP3A5, and CYP3A7. Budesonide is eliminated via Approximately 60% of a budesonide dose is recovered in the urine as the major metabolites 6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone, and their conjugates. No unchanged budesonide is recovered in urine. The half-life of Budesonide is Budesonide has a plasma elimination half life of 2-3. 6h. The terminal elimination half life in asthmatic children 4-6 years old is 2. 3h. The clearance of Budesonide is Budesonide has a plasma clearance of 0. 9-1. 8L/min. The 22R form has a clearance of 1. 4L/min while the 22S form has a clearance of 1. 0L/min. The clearance in asthmatic children 4-6 years old is 0. 5L/min. Budesonide toxicity includes Acute overdose of corticosteroids is rare, however prolonged high dosing of corticosteroids can lead to hypercorticism and adrenal axis suppression. In the case of overdose, reduce the dosage of corticosteroids temporarily. A 200mg oral dose is lethal to female mice while a 400mg oral dose is lethal to male mice. Brand names of Budesonide include Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris. No synonyms are available for Budesonide. Budesonide summary: It is Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis. Pegcetacoplan summary: It is Summary not found. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Budesonide

Drug A is Olaratumab. Drug B is Evolocumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Olaratumab is combined with Evolocumab. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Olaratumab is indicated for Olaratumab is indicated, in combination with doxorubicin, for the treatment of adult patients with advanced or mestastatic soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. Evolocumab is indicated for Evolocumab is indicated in adult patients with established cardiovascular disease to reduce the risk of myocardial infarction, stroke, and coronary revascularization. It is also indicated as an adjunct to diet, alone or in combination with other hypolipidemic treatments, in adults with primary hyperlipidemia (and in pediatric patients ≥10 years old with heterozygous familial hypercholesterolemia) to reduce LDL-C. In addition, it is indicated adjunctly to other hypolipidemic treatments in patients ≥10 years old with homozygous familiar hypercholesterolemia to reduce LDL-C. Olaratumab pharmacodynamics: It exerts an anti-tumor activity in vivo and in vitro against selected sarcoma cells by inhibiting tumor growth by binding to PDGFR-alpha that is present on several types of cancer on transformed cells and in tumor stroma. Olaratumab antibody binding leads to inhibition of ligand-dependent signaling in PDGFR(alpha)-expressing tumor cells, as well as stromal cells in the tumor microenviroment that are dependent on PDGFR(alpha) signaling. When used in a combination therapy with doxorubicin, olaratumab improves progression-free survival in patients with advanced soft-tissue sarcoma. Evolocumab pharmacodynamics: No pharmacodynamics available. The mechanism of action of Olaratumab is that it Olaratumab blocks ligand-induced tumor cell proliferation, and inhibits receptor autophosphorylation and ligand-induced phosphorylation of the downstream signaling molecules protein kinase B (Akt) and mitogen-activated protein kinase. PDGFR signalling is a type of tyrosine kinase-mediated pathway that normally regulates cell growth, chemotaxis, and mesenchymal stem cell differentiation. It also promotes internalization of PDGFR thus alters the surface levels of PDGFR. The mechanism of action of Evolocumab is that it Evolocumab is a human IgG monoclonal antibody which targets PCSK9 (proprotein convertase subtilisin/kexin type 9). PCSK9 is a serine protease produced by the liver which binds LDL receptors and creates a complex to be targeted for lysosomal degradation. LDL receptors typically bind LDL-cholesterol ("bad" cholesterol) for cellular reuptake, therefore the formation of these complexes with PCSK9 inhibits LDL receptor recycling to the cell surface, resulting in decreased cellular reuptake of LDL-C and increased levels of free LDL-C in the plasma. Individuals with familial hypercholesterolemia often may have "gain of function" mutations in the PCSK9 molecules in their body, resulting in increased LDL-C plasma levels and a consequent cardiovascular risk. Evolocumab is able to bind both the normal PCSK9 and the "gain of function" mutant, D374Y. The exact mechanism of the binding has not been published, however the precursor molecule, mAb1, is indicative of the interaction. The mAb1 molecule binds on the catalytic site of PCSK9 next to the binding site for the LDL receptor and creates hydrogen bonds and hydrophobic interactions, resulting in the steric inhibition of binding between PCSK9 and the LDL receptor. Because the formation of complexes between LDL receptor and PCSK9 are prevented, the internalized LDL receptors are less likely to be degrated by lysosomes and may recycle to the surface of the cell to serve their function of removing LDL from the blood. No absorption information is available for Olaratumab. Evolocumab absorption: Total bioavailability from subcutaneous injection was 82% in cynomolgus monkeys. The volume of distribution of Olaratumab is 7. 7 L at steady state. No volume of distribution information is available for Evolocumab. No protein binding information is available for Evolocumab. Olaratumab metabolism: Mainly degraded nonspecifically by proteolytic enzymes. No metabolism information is available for Evolocumab. Olaratumab is eliminated via No route of elimination available. Evolocumab is eliminated via No route of elimination available. The half-life of Olaratumab is Estimated value of 11 days. The half-life of Evolocumab is No half-life available. The clearance of Olaratumab is Mean value of 0. 56L/day. The clearance of Evolocumab is Evolocumab showed non-linear, dose-dependent clearance in healthy volunteers; clearance decreased with increasing dose. Olaratumab toxicity includes Infusion-related reactions may occur during or after the administration which include bronchospasm, flushing, hypotension, anaphylactic shock, or cardiac arrest. Olaratumab may cause embryo-fetal toxicity based on animal data and its mechanism of action. Other reported adverse effects include neutropenia, leukopenia, anemia, nausea and musculoskeletal pain. No toxicity information is available for Evolocumab. Brand names of Olaratumab include Lartruvo. Brand names of Evolocumab include Repatha. No synonyms are available for Olaratumab. No synonyms are available for Evolocumab. Olaratumab summary: It is Olaratumab is a platelet-derived growth factor receptor alpha blocking antibody used with doxorubicin to treat patients with certain types of soft tissue sarcoma (STS). Evolocumab summary: It is Evolocumab is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody used as an adjunct to LDL cholesterol reducing therapies, aiding in the prevention of cardiovascular events and cardiovascular revascularization procedures. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Olaratumab

Drug A is Acarbose. Drug B is Megestrol acetate. The severity of the interaction is moderate. The therapeutic efficacy of Acarbose can be decreased when used in combination with Megestrol acetate. Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage. Acarbose is indicated for Acarbose is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Megestrol acetate is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). Also used for the palliative management of recurrent, inoperable, or metastatic breast cancer, endometrial cancer, and prostate cancer in Canada and some other countries. Acarbose pharmacodynamics: Acarbose is a complex oligosaccharide that competitively inhibits the ability of brush-border alpha-glucosidase enzymes to break down ingested carbohydrates into absorbable monosaccharides, reducing carbohydrate absorption and subsequent postprandial insulin levels. Acarbose requires the co-administration of carbohydrates in order to exert its therapeutic effect, and as such should be taken with the first bite of a meal three times daily. Given its mechanism of action, acarbose in isolation poses little risk of contributing to hypoglycemia - this risk is more pronounced, however, when acarbose is used in conjunction with other antidiabetic therapies (e. g. sulfonylureas, insulin). Patients maintained on acarbose in addition to other antidiabetic agents should be aware of the symptoms and risks of hypoglycemia and how to treat hypoglycemic episodes. There have been rare post-marketing reports of the development of pneumatosis cystoides intestinalis following treatment with alpha-glucosidase inhibitors - patients experiencing significant diarrhea/constipation, mucus discharge, and/or rectal bleeding should be investigated and, if pneumatosis cystoides intestinalis is suspected, should discontinue therapy. Megestrol acetate pharmacodynamics: Megestrol is a synthetic progestin and has the same physiologic effects as natural progesterone. These effects include induction of secretory changes in the endometrium, increase in basal body temperature, pituitary inhibition, and production of withdrawal bleeding in the presence of estrogen. Mestrogel has slight glucocorticoid activity and very slight mineralocorticoid activity. This drug has no estrogenic, androgenic, or anabolic activity. The precise mechanism of megestrol’s antianorexic and anticachetic effects is unknown. Initially developed as a contraceptive, it was first evaluated in breast cancer treatment in 1967. The mechanism of action of Acarbose is that it Alpha-glucosidase enzymes are located in the brush-border of the intestinal mucosa and serve to metabolize oligo-, tri-, and disaccharides (e. g. sucrose) into smaller monosaccharides (e. g. glucose, fructose) which are more readily absorbed. These work in conjunction with pancreatic alpha-amylase, an enzyme found in the intestinal lumen that hydrolyzes complex starches to oligosaccharides. Acarbose is a complex oligosaccharide that competitively and reversibly inhibits both pancreatic alpha-amylase and membrane-bound alpha-glucosidases - of the alpha-glucosidases, inhibitory potency appears to follow a rank order of glucoamylase > sucrase > maltase > isomaltase. By preventing the metabolism and subsequent absorption of dietary carbohydrates, acarbose reduces postprandial blood glucose and insulin levels. The mechanism of action of Megestrol acetate is that it The precise mechanism by which megestrol acetate produces effects in anorexia and cachexia is unknown at the present time, but its progestin antitumour activity may involve suppression of luteinizing hormone by inhibition of pituitary function. Studies also suggest that the megestrol's weight gain effect is related to its appetite-stimulant or metabolic effects rather than its glucocorticoid-like effects or the production of edema. It has also been suggested that megestrol may alter metabolic pathyways via interferences with the production or action of mediators such as cachectin, a hormone that inhibits adipocyte lipogenic enzymes. Acarbose absorption: The oral bioavailability of acarbose is extremely minimal, with less than 1-2% of orally administered parent drug reaching the systemic circulation. Despite this, approximately 35% of the total radioactivity from a radiolabeled and orally administered dose of acarbose reaches the systemic circulation, with peak plasma radioactivity occurring 14-24 hours after dosing - this delay is likely reflective of metabolite absorption rather than absorption of the parent drug. As acarbose is intended to work within the gut, its minimal degree of oral bioavailability is therapeutically desirable. Megestrol acetate absorption: Variable, but well absorbed orally. No volume of distribution information is available for Acarbose. No volume of distribution information is available for Megestrol acetate. Acarbose is As only 1-2% of an orally administered dose is absorbed into the circulation, acarbose is unlikely to be subject to clinically relevant protein binding. bound to plasma proteins. No protein binding information is available for Megestrol acetate. Acarbose metabolism: Acarbose is extensively metabolized within the gastrointestinal tract, primarily by intestinal bacteria and to a lesser extent by digestive enzymes, into at least 13 identified metabolites. Approximately 1/3 of these metabolites are absorbed into the circulation where they are subsequently renally excreted. The major metabolites appear to be methyl, sulfate, and glucuronide conjugates of 4-methylpyrogallol. Only one metabolite - resulting from the cleavage of a glucose molecule from acarbose - has been identified as having alpha-glucosidase inhibitory activity. Megestrol acetate metabolism: Primarily hepatic. Megestrol metabolites which were identified in urine constituted 5% to 8% of the dose administered. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces. No active metabolites have been identified. Acarbose is eliminated via Roughly half of an orally administered dose is excreted in the feces within 96 hours of administration. What little drug material is absorbed into the systemic circulation (approximately 34% of an orally administered dose) is excreted primarily by the kidneys, suggesting renal excretion would be a significant route of elimination if the parent drug was more readily absorbed - this is further supported by data in which approximately 89% of an intravenously administered dose of acarbose was excreted in the urine as active drug (in comparison to <2% following oral administration) within 48 hours. Megestrol acetate is eliminated via The major route of drug elimination in humans is urine. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces. The half-life of Acarbose is In healthy volunteers, the plasma elimination half-life of acarbose is approximately 2 hours. The half-life of Megestrol acetate is 34 hours. No clearance information is available for Acarbose. No clearance information is available for Megestrol acetate. Acarbose toxicity includes The symptoms of acarbose overdose are likely to be consistent with its adverse effect profile and may therefore include significant gastrointestinal (GI) symptoms (flatulence, distension, etc), although an overdose on an empty stomach (i. e. when not co-administered with food) is less likely to result in these GI symptoms. In the event of an overdose, patients should be instructed to avoid carbohydrate-containing foods for 4-6 hours following administration as these can precipitate the aforementioned GI symptoms. Megestrol acetate toxicity includes No serious unexpected side effects have resulted from studies involving megestrol acetate oral suspension administered in dosages as high as 1200 mg/day. Treatment with megestrol acetate, an orexigenic agent, has also resulted in iatrogenic adrenal suppression. The mechanism is presumably related to the glucocorticoid properties of megestrol acetate [PMID: 12872362]. Brand names of Acarbose include Precose. Brand names of Megestrol acetate include Megace. No synonyms are available for Acarbose. No synonyms are available for Megestrol acetate. Acarbose summary: It is Acarbose is an alpha-glucosidase inhibitor used in adjunctly with diet and exercise for the management of glycemic control in patients with type 2 diabetes mellitus. Megestrol acetate summary: It is Megestrol acetate is a progestin that is administered orally to treat anorexia and cachexia or serious unexplained weight loss and is also used as an antineoplastic agent to treat certain types of malignancy. Answer: Agents that directly or indirectly cause hyperglycaemia as an adverse event may alter the pharmacological response and the therapeutic actions of blood glucose lowering agents when co-administered. Mechanism of the interaction may vary, including decreased insulin secretion, increased adrenaline release, reduced total body potassium, negative effect on glucose metabolism, and drug-induced weight gain leading to increased tissue resistance. Decreased hypoglycaemic effects of antidiabetic therapy may require increased dosage.

Acarbose

Drug A is Belantamab mafodotin. Drug B is Astemizole. The severity of the interaction is moderate. Astemizole may decrease the excretion rate of Belantamab mafodotin which could result in a higher serum level. Bile salt export pump (BSEP/ABCB11) plays a crucial role in the secretion of bile acids from the liver. 1,2,3 For this reason, the concurrent administration of two or more bile salt export pump (BSEP/ABCB11) substrates will compete for the BSEP transporter with bile acids, leading to hepatotoxicity from the accumulation of bile acids or adverse effects from the accumulation of the substrate drugs. Belantamab mafodotin is indicated for Belantamab mafodotin is indicated in the treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Astemizole is indicated for Astemizole was indicated for use in the relieving allergy symptoms, particularly rhinitis and conjunctivitis. It has been withdrawn from the market however due to concerns of arrhythmias. Belantamab mafodotin pharmacodynamics: Belantamab mafodotin treats multiple myeloma through antibody dependant cell mediated cytotoxicity as well as G2/M cell cycle arrest. It has a narrow therapeutic index due to the incidence of adverse effects, and a long duration of action as it is given every 3 weeks. Patients should be counselled regarding the risk of keratopathy. Astemizole pharmacodynamics: Astemizole is a second generation H 1 -receptor antagonist. It does not significantly cross the blood brain barrier and therefore does not cause drowsiness or CNS depression at normal doses. The mechanism of action of Belantamab mafodotin is that it Belantamab mafodotin, or GSK2857916, is an afucosylated monoclonal antibody that targets B cell maturation antigen (BCMA) conjugated to the microtubule distrupter monomethyl auristatin-F (MMAF). Afucosylation of the Fc region of monoclonal antibodies enhances binding to the Fc region, which enhances antibody dependant cell mediated cytoxicity. BCMA is uniquely expressed on CD138-positive myeloma cells. Targeting BCMA allows belantamab mafodotin to be highly selective in its delivery of MMAF to multiple myeloma cells. Belantamab mafodotin binds to BCMA, is internalised into cells, and releases MMAF. The MMAF payload binds to tubulin, stopping the cell cycle at the DNA damage checkpoint between the G2 and M phases, resulting in apoptosis. The mechanism of action of Astemizole is that it Astemizole competes with histamine for binding at H 1 -receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of astemizole to H 1 -receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier and preferentially binds at H1 receptors in the peripehery rather than within the brain, CNS depression is minimal. Astemizole may also act on H 3 -receptors, producing adverse effects. Belantamab mafodotin absorption: Belantamab mafodotin at a dose of 2. 5mg/kg reaches a Cmax of 42 µg/mL, with a Tmax of 0. 78 hours, and an AUC of 4666 µg*h/mL. Astemizole absorption: Rapidly absorbed from the gastrointestinal tract. The volume of distribution of Belantamab mafodotin is The mean steady state volume of distribution of belantamab mafodotin was 11 L. No volume of distribution information is available for Astemizole. Belantamab mafodotin is Monoclonal antibodies are generally not protein bound. bound to plasma proteins. Astemizole is 96. 7% bound to plasma proteins. Belantamab mafodotin metabolism: Monoclonal antibodies are expected to be metabolized to smaller peptides and amino acids. MMAF is expected to be metabolized by oxidation and demethylation, however further data is not readily available. Astemizole metabolism: Almost completely metabolized in the liver and primarily excreted in the feces. Belantamab mafodotin is eliminated via Monoclonal antibodies are eventually phagocytosed and broken down to smaller peptides and amino acids which are eliminated in a similar fashion to other proteins. Monoclonal antibodies are generally not eliminated in the urine, and only a small amount is excreted in bile. Astemizole is eliminated via No route of elimination available. The half-life of Belantamab mafodotin is The terminal half life of belantamab mafodotin was 12 days after the first dose and 14 days at steady state. The half-life of Astemizole is 1 day. The clearance of Belantamab mafodotin is The clearance of belantamab mafodotin was 0. 9 L/day after the first dose and 0. 7 L/day at steady state. No clearance information is available for Astemizole. Belantamab mafodotin toxicity includes Data regarding overdose is not readily available. However, keratopathy was seen in 71% of patients. Astemizole toxicity includes LD 50 =2052mg/kg in mice. Brand names of Belantamab mafodotin include BLENREP. Brand names of Astemizole include No brand names available. No synonyms are available for Belantamab mafodotin. No synonyms are available for Astemizole. Astémizole Astemizole Astemizolum Belantamab mafodotin summary: It is Belantamab mafodotin is an anti B-cell maturation antigen antibody conjugated to a microtubule inhibitor to treat relapsed or refractory multiple myeloma. Astemizole summary: It is Astemizole is a second generation antihistamine used to treat allergy symptoms. Answer: Bile salt export pump (BSEP/ABCB11) plays a crucial role in the secretion of bile acids from the liver. 1,2,3 For this reason, the concurrent administration of two or more bile salt export pump (BSEP/ABCB11) substrates will compete for the BSEP transporter with bile acids, leading to hepatotoxicity from the accumulation of bile acids or adverse effects from the accumulation of the substrate drugs.

Belantamab mafodotin

Drug A is Acalabrutinib. Drug B is Raloxifene. The severity of the interaction is major. The serum concentration of Acalabrutinib can be increased when it is combined with Raloxifene. The subject drug is a CYP3A4 enzyme inhibitor, and the affected drug is metabolized by the CYP3A4 enzyme. Concomitant administration of these agents will decrease the metabolism of the CYP3A4 substrate (affected drug), increasing the serum concentration and therapeutic effect. Drugs with a narrow therapeutic index must be maintained within a specific concentration range in order to be safe and efficacious. An increased concentration of a drug with a narrow therapeutic index may lead to significant adverse effects and toxicity. Acalabrutinib is indicated for Acalabrutinib is currently indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. It has also been recently approved for chronic lymphocytic leukemia and small lymphocytic lymphoma. Raloxifene is indicated for Indicated for the prevention and treatment of osteoporosis in postmenopausal women, as well as prevention and treatment of corticosteroid-induced bone loss. Indicated for the reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis or postmenopausal women with a high risk for invasive breast cancer. Acalabrutinib pharmacodynamics: Acalabrutinib is a Bruton Tyrosine Kinase inhibitor that prevents the proliferation, trafficking, chemotaxis, and adhesion of B cells. It is taken every 12 hours and can cause other effects such as atrial fibrillation, other malignancies, cytopenia, hemorrhage, and infection. Raloxifene pharmacodynamics: Raloxifene belongs to the selective estrogen receptor modulator (SERM) drug class that exhibits estrogenic effects on bone and lipid metabolism while mediating anti-estrogenic effects on uterine endometrium and breast tissues. On skeletal tissues, raloxifene stimulates bone-depositing osteoblasts and inhibits bone-resorbing osteoclasts to augument bone mineral density. Raloxifene produces estrogen-like effects on bone, reducing the resorption of bone and increasing bone mineral density in postmenopausal women, thus slowing the rate of bone loss. In three randomized, placebo-controlled trials in Europe, postmenopausal women receiving raloxifene at variable doses of 30 to 150 mg daily demonstrated significant increases in bone mineral density in the lumbar spine, total hip, femoral neck and total body compared to placebo. In the MORE and RUTH trials, there were fewer incidences of vertebral fractures in postmeopausal women receiving raloxifene compared to placebo. In a eight-week study evaluating short-term effects of raloxifene in healthy postmenopausal women, there was a decrease in the bone turnover markers, such as serum alkaline phosphatase level, serum osteocalcin level and urinary calcium excretion. Raloxifene was shown to inhibit estrogen-dependent proliferation of human breast cancer cells in vitro and development of induced mammary tumors in rats in vivo. In adult female rats, raloxifene produced a greater regression of the mammary gland than tamoxifen. The MORE trial was a multicenter, randomized, double-blind clinical trial that investigated the long-term effects of the drug therapy in European and American postmenopausal women receiving raloxifene for 40 months. Additionally, a reduction in the incidence of invasive breast cancer was also demonstrates in the CORE and RUTH trials. Study findings demonstrated that compared to placebo, the risk of invasive breast cancer was decreased by 76% among postmenopausal women with osteoporosis. There was a decrease in the risk of estrogen receptor-positive breast cancer by 90% but there was no increase in the risk of endometrial cancer. Unlike hormone replacement therapy, raloxifene does not mediate proliferative or stimulatory effects on endometrial tissue. Findings from both animal and human studies demonstrated no significant changes in the histologic appearance of the endometrium. Raloxifene promotes estrogen-like effects on lipid metabolism. In a European trial that evaluated lipid profiles following raloxifene therapy over the 24-month period, there were significant decreases in the serum concentrations of total and low-density lipoprotein (LDL) cholesterol over a 24-month period of raloxifene therapy. Raloxifene is not associated with causing alterations in the serum levels of HDL cholesterol or triglycerides. As the HDL choesterol level is considered a strong inverse predictor of cardiovascular disease in women, the cardioprotective effects of raloxifene were questioned. Due to limited data on the long-term trials, it is not possible to determine whether the small lipid effects produced by raloxifene correlate with a smaller degree of cardioprotective activity compared with hormone replacement therapy. The mechanism of action of Acalabrutinib is that it Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. Subsequently, relapse is common in MCL patients and ultimately represents disease progression. Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas are the body's own B-lymphocytes (B-cells). Bruton Tyrosine Kinase (BTK) is a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Acalabrutinib is a small molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity. As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor, acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates highter selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1. In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects - in theory - because of the drug's minimized off target effects. The mechanism of action of Raloxifene is that it Raloxifene is a selective estrogen receptor modulator that acts as both an estrogen agonist and antagonist via differential effects on the tissue-specific estrogen receptors. Based on the findings of competitive binding assays, raloxifene displays binding affinity that is similar to that of estradiol, the predominant circulating estrogen. Estrogens play variable roles at different tissues in females, including the bone, breasts, uterus and liver, by binding to the steroid nuclear hormone receptors, Estrogen Receptor alpha (ERα) or Estrogen Receptor beta (ERβ). These receptors are normally bound to the Heat Shock Protein 90 (Hsp90) when unbound to the ligand. Ligand binding induces a conformational change in the receptor that promotes dissociation of the receptor from Hsp90, dimerization and translocation into the nucleus. This movement into the nucleus allows the receptor to bind to genomic locations based on sequence recognition of the DNA binding domain, also known as the Estrogen Response Elements (EREs). In bones, endogenous estrogens normally modulate multiple DNA response elements, including the gene-encoding transforming growth factor-β3 (TGF-β3), which is a cytokine embedded in the bone matrix. TGF-β3 plays an important role in bone remodelling by working with other cytokines to induce production of osteoblasts, such as IL-6, and attenuate the activity of osetoclasts. Estrogens typically maintain the bone integrity by inhibiting the cytokines that recruit osteoclasts and oppose the bone-resorbing, Ca2+-mobilizing action of parathyroid hormone. In contrast, estrogens promote osteoblast proliferation, augment the production of TGF-β3 and bone morphogenic proteins, and inhibit apoptosis. Mimicking the action of endogenous estrogen in bone tissues, raloxifene binds to the estrogen receptor to influence gene transcription through interactions with the estrogen response element (ERE) and a distinct DNA target, the raloxifene response element (RRE). It occupies the same ER ligand binding site as estrogen. Upon binding, raloxifene induces a conformational change of the receptor, allowing mediation of direct binding to transcriptional elements by accessory proteins. Increased expression of bone matrix proteins, such as alkaline phosphatase, osteonectin, osteocalcin and collagen may be seen. The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promotors. In breast tissues, raloxifene acts as an estrogen receptor antagonist to attenuate the estrogen-dependent proliferative effects of epithelial cell expansion. In addition to the antiproliferative effects, raloxifene prevents the production of cytokines and recruitment of macrophages and lymphocytes into tumor mass. Acalabrutinib absorption: The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0. 75 hours. Raloxifene absorption: Raloxifene is well absorbed from the gastrointestinal tract, with approximately 60% fo the drug being absorbed following oral administration. Due to the extensive first-pass hepatic metabolism that involves glucuronide conjugation, the absolute oral bioavailability of raloxifene is about 2%. Following oral ingestion of a single dose or multiple dose of raloxifen in healthy postmenopausal women, the mean peak plasma concentrations (Cmax) were 0. 50 and 1. 36 ng/mL, respectively, and the AUC values were 27. 2 and 24. 2 ngxhr/mL, respectively. The time to reach Cmax following a single or multiple oral doses were 27. 7 and 32. 5 hours, respectively. Although not clinically significant, oral ingestion of raloxifene with high-fat meals is thought to increase the systemic bioavailability of the drug by increasnig the peak plasma concentrations (Cmax) and AUC by 28% and 16%, respectively. The volume of distribution of Acalabrutinib is The mean steady-state volume of distribution is approximately 34 L. The volume of distribution of Raloxifene is Following oral administration of single doses randing from 30 to 150 mg in postmenopausal women, the volume of distribution was about 2348 L/kg. Following oral administration of multiple doses, the value increased to 2853 L/kg. Raloxifene is widely distributed in the tissues. It is not known whether raloxifene is excreted in human milk. Acalabrutinib is Reversible binding of acalabrutinib to human plasma protein is approximately 97. 5%. The in vitro mean blood-to-plasma ratio is about 0. 7. In vitro experiments at physiologic concentrations show that acalabrutinib can be 93. 7% bound to human serum albumin and 41. 1% bound to alpha-1-acid glycoprotein. bound to plasma proteins. Raloxifene is About 95% of raloxifene and its glucuronide metabolites are bound to plasma proteins. Although this is a relatively high protein binding profile, in vitro studies suggest that raloxifene and its metabolites do not significantly interact with binding of highly protein-bound drugs. FDA Label still advises patients to use raloxifene with caution co-administering with other highly protein-bound drugs. bound to plasma proteins. Acalabrutinib metabolism: Acalabrutinib is mainly metabolized by CYP3A enzymes. ACP-5862 is identified to be the major active metabolite in plasma with a geometric mean exposure (AUC) that is about 2-3 times greater than the exposure of acalabrutinib. ACP-5862 is about 50% less potent than acalabrutinib in regards to the inhibition of BTK. Raloxifene metabolism: Raloxifene is reported to undergo metabolism in the intestines and liver devoid of cytochrome P450 pathway. It is extensively metabolized, where less than 1% of the total dose exists as unchanged compound. It mainly undergoes first-pass metabolism to form glucuronide conjugates, raloxifene-4'-glucuronide (raloxifene-4'-β-glucuronide), raloxifene-6-glucuronide (raloxifene-6-β-glucuronide), and raloxifene-6,4'-diglucuronide. No other metabolites have been detected in human plasma. The terminal log-linear portions of the plasma concentration curves for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites. Acalabrutinib is eliminated via After administration of a single 100 mg radiolabelled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine. An irradiated dose of acalabrutinib was 34. 7% recovered as the metabolite ACP-5862; 8. 6% was recovered as unchanged acalabrutinub; 10. 8 was recovered as a mixture of the M7, M8, M9, M10, and M11 metabolites; 5. 9% was the M25 metabolite; 2. 5% was recovered as the M3 metabolite. Raloxifene is eliminated via Raloxifene predominantly undergoes fecal excretion, with less than 0. 2% of the dose being excreted in the urine as unchanged form of the compound and less than 6% of the dose being excreted as glucuronide conjugates. Co-administration with cholestyramine, a bile acid sequestrant, was shown to reduce the enterohepatic recycling of raloxifene by 60%. The half-life of Acalabrutinib is After administering a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life of the drug was found to be 0. 9 (with a range of 0. 6 to 2. 8) hours. The half-life of the active metabolite, ACP-5862, is about 6. 9 hours. The half-life of Raloxifene is The average plasma elimination half-life of raloxifene ranges from 27 to 32 hours. The prolonged half-life has been attributed to the drug's reversible systemic metabolism and significant enterohepatic cycling. The clearance of Acalabrutinib is Acalabrutinib's mean apparent oral clearance (CL/F) is observed to be 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis. The clearance of Raloxifene is Following intravenous administration, raloxifene was shown to be cleared at a rate approximating hepatic blood flow. The apparent oral clearance is reported to be 44. 1 L/kgxhr. The clearance can range from 40 to 60L/kgxhr following chronic dosing. In healthy postmenopausal women receiving multiple oral dose, the mean clearance was 47. 4 L/kgxhr. Apparent clearance can be reduced by 56% in patients with hepatic impairment. Acalabrutinib toxicity includes Data regarding the toxicity of acalabrutinib is not readily available. Raloxifene toxicity includes LD 50 and Overdose The oral LD 50 value in rats is > 5000 mg/kg, which is about 810 times the human dose. In monkeys, no mortality was seen after a single oral dose of 1000 mg/kg. No cases of raloxifene overdose have been reported during clinical trials. A rare postmarketing report of a non-fatal overdose after oral ingestion of 1. 5 g has been reported. Common adverse events of leg cramps, hot flushes, and dizziness have been reported with the use of raloxifene at doses of greater than 180 mg. More serious adverse event of venous thromboembolic events were observed with raloxifene. Two 18-month-old children accidentally ingested 180 mg of raloxifene and symptoms of ataxia, dizziness, vomiting, rash, diarrhea, tremor, flushing, and elevated alkaline phosphatase levels were reported. There is no known antidote for raloxifene. Nonclinical Toxicology In a two-year mouse carcinogenicity study at raloxifene doses that are higher than the human therapeutic doses, there was an increased incidence of benign and malignant ovarian tumors of granulosa or theca cell origin. Another study showed an increased incidence of testicular interstitial cell tumors, prostatic adenomas, adenocarcinomas, and prostatic leiomyoblastoma in male mice receiving doses higher than human therapeutic doses. There was no evidence of the genotoxic potential of raloxifene in bacterial mutagenicity assays, in vitro rat DNA assays, or other in vitro rodent cell line assays. When assessing effects on the reproductive system of male and female rats, raloxifene caused lack of pregnancy and disruptions in estrous cycles and inhibited ovulation at dose of 0. 1 to 10 mg/kg/day. Administration of raloxifene during the preimplantation period at doses greater than 0. 1 mg/kg resulted in delayed and disrupted embryo implantation, further leading to prolonged gestation and reduced litter size. There were no effects on sperm production or quality or reproductive performance in male rats. The effects on the fertility by raloxifene were reversible. Use in special populations The use of raloxifene in pregnant or nursing women is not advised. Although there are no specific dosing adjustment guidelines, caution should be undertaken when administering raloxifene in geriatric patients or patients with renal or hepatic impairment. Brand names of Acalabrutinib include Calquence. Brand names of Raloxifene include Evista, Optruma. No synonyms are available for Acalabrutinib. No synonyms are available for Raloxifene. Raloxifene Raloxifeno Raloxifenum Acalabrutinib summary: It is Acalabrutinib is a Bruton tyrosine kinase inhibitor used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Raloxifene summary: It is Raloxifene is a selective estrogen receptor modulator that is used to prevent and treat osteoporosis and reduce the risk of invasive breast cancer in high-risk postmenopausal women. Answer: The subject drug is a CYP3A4 enzyme inhibitor, and the affected drug is metabolized by the CYP3A4 enzyme. Concomitant administration of these agents will decrease the metabolism of the CYP3A4 substrate (affected drug), increasing the serum concentration and therapeutic effect. Drugs with a narrow therapeutic index must be maintained within a specific concentration range in order to be safe and efficacious. An increased concentration of a drug with a narrow therapeutic index may lead to significant adverse effects and toxicity.

Acalabrutinib

Drug A is Oxytocin. Drug B is Papaverine. The severity of the interaction is minor. The risk or severity of QTc prolongation can be increased when Oxytocin is combined with Papaverine. The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e. g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. Oxytocin is indicated for Administration of exogenous oxytocin is indicated in the antepartum period to initiate or improve uterine contractions for vaginal delivery in situations where there is fetal or maternal concern. For example, It may be used to induce labor in cases of Rh sensitization, maternal diabetes, preeclampsia at or near term, and when delivery is indicated due to prematurely ruptured membranes. Importantly, oxytocin is not approved or indicated for elective induction of labor. Oxytocin may be used to reinforce labor in select cases of uterine inertia and as adjunctive therapy in the management of incomplete or inevitable abortion. In the postpartum period, oxytocin may be used to induced contractions in the 3rd stage of labor and to control postpartum bleeding or hemorrhage. Papaverine is indicated for the treatment of impotence and vasospasms. Oxytocin pharmacodynamics: Oxytocin is a nonapeptide, pleiotropic hormone that exerts important physiological effects. It is most well known to stimulate parturition and lactation, but also has important physiological influences on metabolic and cardiovascular functions, sexual and maternal behaviour, pair bonding, social cognition, and fear conditioning. It is worth noting that oxytocin receptors are not limited to the reproductive system but can be found in many peripheral tissues and in central nervous system structures including the brain stem and amygdala. Papaverine pharmacodynamics: Papaverine is a nonxanthine phosphodiesterase inhibitor for the relief of cerebral and peripheral ischemia associated with arterial spasm and myocardial ischemia complicated by arrhythmias. The main actions of Papaverine are exerted on cardiac and smooth muscle. Like qathidine, Papaverine acts directly on the heart muscle to depress conduction and prolong the refractory period. Papaverine relaxes various smooth muscles. This relaxation may be prominent if spasm exists. The muscle cell is not paralyzed by Papaverine and still responds to drugs and other stimuli causing contraction. The antispasmodic effect is a direct one, and unrelated to muscle innervation. Papaverine is practically devoid of effects on the central nervous system. Papaverine relaxes the smooth musculature of the larger blood vessels, especially coronary, systemic peripheral, and pulmonary arteries. The mechanism of action of Oxytocin is that it Oxytocin plays a vital role in labour and delivery. The hormone is produced in the hypothalamus and is secreted from the paraventricular nucleus to the posterior pituitary where it is stored. It is then released in pulses during childbirth to induce uterine contractions. The concentration of oxytocin receptors on the myometrium increases significantly during pregnancy and reaches a peak in early labor. Activation of oxytocin receptors on the myometrium triggers a downstream cascade that leads to increased intracellular calcium in uterine myofibrils which strengthens and increases the frequency of uterine contractions. In humans, most hormones are regulated by negative feedback; however, oxytocin is one of the few that is regulated by positive feedback. The head of the fetus pushing on the cervix signals the release of oxytocin from the posterior pituitary of the mother. Oxytocin then travels to the uterus where it stimulates uterine contractions. The elicited uterine contractions will then stimulate the release of increasing amounts of oxytocin. This positive feedback loop will continue until parturition. Since exogenously administered and endogenously secreted oxytocin result in the same effects on the female reproductive system, synthetic oxytocin may be used in specific instances during the antepartum and postpartum period to induce or improve uterine contractions. The mechanism of action of Papaverine is that it Perhaps by its direct vasodilating action on cerebral blood vessels, Papaverine increases cerebral blood flow and decreases cerebral vascular resistance in normal subjects; oxygen consumption is unaltered. These effects may explain the benefit reported from the drug in cerebral vascular encephalopathy. Oxytocin absorption: Oxytocin is administered parenterally and is fully bioavailable. It takes approximately 40 minutes for oxytocin to reach steady-state concentrations in the plasma after parenteral administration. No absorption information is available for Papaverine. No volume of distribution information is available for Oxytocin. No volume of distribution information is available for Papaverine. No protein binding information is available for Oxytocin. Papaverine is ~90% bound to plasma proteins. Oxytocin metabolism: Oxytocin is rapidly removed from the plasma by the liver and kidney. The enzyme oxytocinase is largely responsible for the metabolism and regulation of oxytocin levels in pregnancy and only a small percentage of the neurohormone is excreted in the urine unchanged. Oxytocinase activity increases throughout pregnancy and peaks in the plasma, placenta and uterus near term. The placenta is a key source of oxytocinase during gestation and produces increasing amounts of the enzyme in response to increasing levels of oxytocin produced by the mother. Oxytocinase activity is also expressed in mammary glands, heart, kidney, and the small intestine. Lower levels of activity can be found in the brain, spleen, liver, skeletal muscle, testes, and colon. The level of oxytocin degradation is negligible in non-pregnant women, men, and cord blood. No metabolism information is available for Papaverine. Oxytocin is eliminated via The enzyme oxytocinase is largely responsible for the metabolism and regulation of oxytocin levels in pregnancy; only a small percentage of the neurohormone is excreted in the urine unchanged. Papaverine is eliminated via No route of elimination available. The half-life of Oxytocin is The plasma half-life of oxytocin ranges from 1-6 minutes. The half-life is decreased in late pregnancy and during lactation. The half-life of Papaverine is 0. 5-2 hours. The clearance of Oxytocin is In a study that observed 10 women who were given oxytocin to induce labor, the mean metabolic clearance rate was 7. 87 mL/min. No clearance information is available for Papaverine. Oxytocin toxicity includes Administration of supratherapeutic doses of exogenous oxytocin can lead to myocardial ischemia, tachycardia, and arrhythmias. High doses can also lead to uterine spasms, hypertonicity, or rupture. Oxytocin has antidiuretic properties, thus, high daily doses (as a single dose or administered slowly over 24 hours) may lead to extreme water intoxication resulting in maternal seizures, coma, and even death. The risk of antidiuresis and water intoxication in the mother appears to be greater when fluids are given orally. No toxicity information is available for Papaverine. Brand names of Oxytocin include Pitocin. Brand names of Papaverine include No brand names available. No synonyms are available for Oxytocin. No synonyms are available for Papaverine. Oxytocin summary: It is Oxytocin is a recombinant hormone used to induce or strengthen uterine contractions in pregnant women to aid in labor and delivery or to control postpartum bleeding. Papaverine summary: It is Papaverine is an alkaloid used to treat many types of smooth muscle spasms such as "vascular spasms" associated with acute myocardial infarction and angina pectoris, as well as "visceral spasms". Answer: The subject drug may prolong the QTc interval. The affected drug is known to have a moderate risk of prolonging the QTc interval. Concomitant administration of multiple medications that may prolong the QTc interval is a significant risk factor for the development of torsades de pointes (TdP), a potentially fatal ventricular arrhythmia that can arise secondary to QTc prolongation. Other risk factors for the development of TdP include female sex, advanced age, low electrolyte concentrations (e. g. hypokalemia), concomitant diuretic use, bradycardia, and baseline cardiovascular disease. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females.

Oxytocin

Drug A is Risankizumab. Drug B is Daunorubicin. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Daunorubicin is combined with Risankizumab. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Risankizumab is indicated for Risankizumab is indicated to treat: moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. active psoriatic arthritis in adults. In Canada and Europe, it may be used alone or in combination with a conventional non-biologic disease-modifying antirheumatic drug (cDMARD) (e. g., methotrexate). moderately to severely active Crohn's disease in adults. In Canada, it is used in patients who have had an inadequate response, intolerance, or demonstrated dependence on corticosteroids; or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies. Daunorubicin is indicated for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults. Daunorubicin is indicated in combination with cytarabine for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older. Risankizumab pharmacodynamics: Risankizumab works to suppress the inflammatory effects of interleukin (IL)-23. It inhibits the release of pro-inflammatory cytokines and chemokines. In vitro, risankizumab blocked IL-17 production; however, risankizumab does not actually bind to IL-17. Daunorubicin pharmacodynamics: Daunorubicin is an anthracycline antibiotic and antineoplastic agent. It acts by inhibiting cellular reproduction through interference with DNA replication although it may contribute to the induction of cell death by increasing oxidative stress through the generation of reactive oxygen species and free radicals. As an antineoplastic agent, daunorubicin carries significant toxicities including cytopenias, hepatotoxicity, and extravasation reactions. Like other anthracyclines, daunorubicin also exhibits cardiotoxicity in proportion with the cumulative dose received over time. The mechanism of action of Risankizumab is that it Interleukin (IL)-23 is a pro-inflammatory cytokine implicated in various chronic inflammatory disorders, such as plaque psoriasis, psoriatic arthritis, and Crohn's disease. IL-23 binds to the IL-23 receptor to activate the IL-23/Th17 axis, which is responsible for mediating T cell-mediated immune responses and inflammation. The IL-23/Th17 axis triggers the differentiation of Th-17 and Th-22 cells and induces the release of inflammatory cytokines and chemokines such as IL-17. While the IL-23/Th17 axis serves a critical role in protection against pathogens, it is also involved in chronic, autoimmune, inflammatory disorders. IL-23 is made up of two subunits, p19 and p40: p19 is specific to IL-23 and p40 is present on both IL-12 and IL-23. Risankizumab binds to the p19 subunit of IL-23 with high affinity and neutralizes it, thereby preventing its interaction with the IL-23 receptor and activation of IL-23 signalling cascades. The mechanism of action of Daunorubicin is that it Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Daunorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. Risankizumab absorption: Drug plasma concentrations increased dose-proportionally after subcutaneous administration of a single dose over the dose range from 18 mg to 360 mg and intravenous administration over a dose range from 200 mg to 1800 mg via a 3-hour infusion. In patients with plaque psoriasis who received a subcutaneous dose of 150 mg risankizumab, steady-state peak concentration (Cmax ) and trough concentration (C trough ) were 12 mcg/mL and 2 mcg/mL, respectively. In subjects with Crohn’s disease treated with 600 mg intravenous induction dose at Weeks 0, 4, and 8, followed by 180 mg or 360 mg subcutaneous maintenance dose at Week 12 and every 8 weeks thereafter, the median Cmax and Ctrough are estimated to be 156 mcg/mL and 38. 8 mcg/mL, respectively, during Weeks 8-12; and the steady state median Cmax and Ctrough are estimated to be 14. 0 mcg/mL and 4. 1 mcg/mL, respectively for 180 mg or 28. 0 mcg/mL and 8. 1 mcg/mL, respectively, for 360 mg, during Weeks 40-48. The absolute bioavailability of risankizumab was approximately 74 to 89% following subcutaneous injection. In healthy subjects, following administration of a single subcutaneous dose, Cmax was reached by 3 to 14 days. Daunorubicin absorption: Daunorubicin was found to have a tmax of 2 h and a cmax of 24. 8 μg/mL after a 90 min infusion of the liposomal formulation at a dose of 44 mg/m. The volume of distribution of Risankizumab is The estimated steady-state volume of distribution (inter-subject CV%) was 11. 2 L (34%) in subjects with plaque psoriasis, and 7. 68 L (64%) in subjects with Crohn’s disease. The volume of distribution of Daunorubicin is Daunorubicin has a steady-state volume of distribution of 1. 91 L/m reported with the liposomal formulation. The average volume of distribution reported for the liposomal formulation is 6. 6 L. Risankizumab is No information is available. bound to plasma proteins. No protein binding information is available for Daunorubicin. Risankizumab metabolism: The metabolic pathway of risankizumab has not been fully characterized. As a humanized IgG1 monoclonal antibody, it is likely to be catabolized into small peptides and amino acids in the same way as endogenous IgG. No metabolism information is available for Daunorubicin. Risankizumab is eliminated via As an IgG1 monoclonal antibody, risankizumab is not expected to be filtered by glomerular filtration in the kidneys or to be excreted as an intact molecule in the urine. Daunorubicin is eliminated via Daunorubicin is eliminated hepatically. 40% of daunorubicin is excreted in the bile while 25% is excreted in an active form (daunorubicin or daunorubicinol) in the urine. In the liposomal formulation, only 9% of active molecules are excreted in the urine. The half-life of Risankizumab is The terminal elimination half-life was approximately 28 days in patients with plaque psoriasis and 21 days in patients with Crohn’s disease. The half-life of Daunorubicin is Daunorubicin has been determined to have a terminal half-life of 18. 5 h (+/- 4. 9). Daunorubicinol, the primary active metabolite has been determined to have a terminal half-life of 26. 7 h (+/- 12. 8). The mean half-life of elimination of liposomal daunorubicin has been reported to be 22. 1 h in pharmacokinetic studies and 31. 5 h in official FDA labeling. The clearance of Risankizumab is The estimated systemic clearance (inter-subject CV%) was 0. 31 L/day (24%) in patients with plaque psoriasis and 0. 30 L/day (34%) in patients with Crohn’s disease. The clearance of Daunorubicin is Daunorubicin has a clearance of 68. 4 mL/h/m determined using the liposomal formulation. Risankizumab toxicity includes The NOAEL was 50 mg/kg in monkeys following intravenous or subcutaneous administration. There is no information available regarding the overdose of risankizumab. No toxicity information is available for Daunorubicin. Brand names of Risankizumab include Skyrizi 150 Mg Dose Pack. Brand names of Daunorubicin include Cerubidine, Vyxeos. No synonyms are available for Risankizumab. No synonyms are available for Daunorubicin. Daunomycin Daunorubicin liposomal Daunorubicina Daunorubicine Daunorubicinum Leukaemomycin C Rubidomycin Risankizumab summary: It is Risankizumab is an interleukin-23 antagonist used to treat plaque psoriasis, psoriatic arthritis, and Crohn's disease in adults. Daunorubicin summary: It is Daunorubicin is an anthracycline aminoglycoside used to induce remission of nonlymphocytic leukemia and acute lymphocytic leukemia. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Risankizumab

Drug A is Budesonide. Drug B is Pravastatin. The severity of the interaction is moderate. Pravastatin may decrease the excretion rate of Budesonide which could result in a higher serum level. Bile salt export pump (BSEP/ABCB11) plays a crucial role in the secretion of bile acids from the liver. 1,2,3 For this reason, the concurrent administration of two or more bile salt export pump (BSEP/ABCB11) substrates will compete for the BSEP transporter with bile acids, leading to hepatotoxicity from the accumulation of bile acids or adverse effects from the accumulation of the substrate drugs. Budesonide is indicated for Budesonide extended-release capsules are indicated for the treatment and maintenance of mild to moderate Crohn’s disease. Various inhaled budesonide products are indicated for prophylactic therapy in asthma and to reduce exacerbations of COPD. A budesonide nasal spray is available over the counter for symptoms of hay fever and upper respiratory allergies. Extended-release capsules are indicated to induce remission of mild to moderate ulcerative colitis and a rectal foam is used for mild to moderate distal ulcerative colitis. In addition, a delayed-release capsule formulation of budesonide is indicated to reduce proteinuria in adults with IgA nephropathy at risk of rapid disease progression. Budesonide is indicated to treat eosinophilic esophagitis (EoE): For this indication, it is only approved for use in adults in Europe while it is approved for short-term use (12 weeks) in patients 11 years of age and older in the US. Pravastatin is indicated for Pravastatin is indicated for primary prevention of coronary events hypercholesterolemic patients without clinical evidence of coronary heart disease. Its use includes the reduction of risk on myocardial infarction, undergoing myocardial revascularization procedures and cardiovascular mortality. As well, pravastatin can be used as a secondary prevention agent for cardiovascular events in patients with clinically evident coronary heart disease. This indication includes the reduction of risk of total mortality by reducing coronary death, myocardial infarction, undergoing myocardial revascularization procedures, stroke, and stroke/transient ischemic attack as well as to slow the progression of coronary atherosclerosis. The term cardiovascular events correspond to all the incidents that can produce damage to the heart muscle including the interruption of blood flow. As adjunctive therapy to diet, pravastatin is used in: Patients with primary hypercholesterolemia and mixed dyslipidemias including hyperlipidemia type IIa and IIb. Patients with elevated serum triglycerides including type IV hyperlipidemia. Patients with heterozygous familial hypercholesterolemia in patients over 8 years of age with low-density lipoprotein (LDL) cholesterol higher than 190 mg/dl after diet modifications or LDL levels higher than 160 mg/dl and familial history of premature cardiovascular diseases or at least two cardiovascular risk factors. In patients that do not respond adequately to diet, pravastatin is used to treat patients with primary dysbetalipoproteinemia (type III hyperlipidemia). Dyslipidemia is defined as an elevation of plasma cholesterol, triglycerides or both as well as to the presence of low levels of high-density lipoprotein. This condition represents an increased risk for the development of atherosclerosis. Budesonide pharmacodynamics: Budesonide is a glucocorticoid used to treat respiratory and digestive conditions by reducing inflammation. It has a wide therapeutic index, as dosing varies highly from patient to patient. Patients should be counselled regarding the risk of hypercorticism and adrenal axis suppression. Pravastatin pharmacodynamics: The action of pravastatin on the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase produces an increase in the expression of hepatic LDL receptors which in order decreases the plasma levels of LDL cholesterol. The effect of pravastatin has been shown to significantly reduce the circulating total cholesterol, LDL cholesterol, and apolipoprotein B. As well, it modestly reduces very low-density-lipoproteins (VLDL) cholesterol and triglycerides while increasing the level of high-density lipoprotein (HDL) cholesterol and apolipoprotein A. In clinical trials with patients with a history of myocardial infarction or angina with high total cholesterol, pravastatin decreased the level of total cholesterol by 18%, decreased of LDL by 27%, decreased of triglycerides by 6% and increased of high-density lipoprotein (HDL) by 4%. As well, there was reported a decrease in risk of death due to coronary disease of 24%. When coadministered with cholestyramine, pravastatin can reduce by 50% the levels of LDL and slow the progression of atherosclerosis and the risk of myocardial infarction and death. The mechanism of action of Budesonide is that it The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. The mechanism of action of Pravastatin is that it Pravastatin is a specific inhibitor of the hepatic HMG-CoA reductase in humans. The inhibition of this enzyme produces a reduction in cholesterol biosynthesis as HMG-CoA reductase activity is an early-limiting step in cholesterol biosynthesis. The inhibitory mechanism of action produces a reduction in cholesterol synthesis which in order has been observed to increase the number of LDL receptors on cell surfaces and an enhancement in receptor-mediated metabolism of LDL and clearance. On the other hand, pravastatin-driven inhibition of LDL production inhibits hepatic synthesis of VLDL as the LDL is the precursor for these molecules. Budesonide absorption: Extended release oral capsules are 9-21% bioavailable. A 9mg dose reaches a Cmax of 1. 50±0. 79ng/mL with a Tmax of 2-8h and an AUC of 7. 33ng*hr/mL. A high fat meal increases the Tmax by 2. 3h but otherwise does not affect the pharmacokinetics of budesonide. 180-360µg metered inhaled doses of budesonide are 34% deposited in the lungs, 39% bioavailable, and reach a Cmax of 0. 6-1. 6nmol/L with a Tmax of 10 minutes. A 1mg nebulized dose is 6% bioavailable, reaching a Cmax of 2. 6nmol/L with a Tmax of 20 minutes. A 9mg oral extended release tablet reaches a Cmax of 1. 35±0. 96ng/mL with a Tmax of 13. 3±5. 9h and an AUC of 16. 43±10. 52ng*hr/mL. Budesonide rectal foam 2mg twice daily has an AUC of 4. 31ng*hr/mL. Pravastatin absorption: Pravastatin is absorbed 60-90 min after oral administration and it presents a low bioavailability of 17%. This low bioavailability can be presented due to the polar nature of pravastatin which produces a high range of first-pass metabolism and incomplete absorption. Pravastatin is rapidly absorbed from the upper part of the small intestine via proton-coupled carrier-mediated transport to be later taken up in the livery by the sodium-independent bile acid transporter. The reported time to reach the peak serum concentration in the range of 30-55 mcg/L is of 1-1. 5 hours with an AUC ranging from 60-90 mcg. h/L. The volume of distribution of Budesonide is The volume of distribution of budesonide is 2. 2-3. 9L/kg. The volume of distribution of Pravastatin is The reported steady-state volume of distribution of pravastatin is reported to be of 0. 5 L/kg. This pharmacokinetic parameter in children was found to range from 31-37 ml/kg. Budesonide is Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. Budesonide is 85-90% protein bound in plasma. bound to plasma proteins. Pravastatin is Due its polarity, pravastatin binding to plasma proteins is very limited and the bound form represents only about 43-48% of the administered dose. However, the activity of p-glycoprotein in luminal apical cells and OATP1B1 produce significant changes to pravastatin distribution and elimination. bound to plasma proteins. Budesonide metabolism: Budesonide is 80-90% metabolized at first pass. Budesonide is metabolized by CYP3A to its 2 major metabolites, 6beta-hydroxybudesonide and 16alpha-hydroxyprednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. CYP3A4 is the strongest metabolizer of budesonide, followed by CYP3A5, and CYP3A7. Pravastatin metabolism: After initial administration, pravastatin undergoes extensive first-pass extraction in the liver. However, pravastatin's metabolism is not related to the activity of the cytochrome P-450 isoenzymes and its processing is performed in a minor extent in the liver. Therefore, this drug is highly exposed to peripheral tissues. The metabolism of pravastatin is ruled mainly by the presence of glucuronidation reactions with very minimal intervention of CYP3A enzymes. After metabolism, pravastatin does not produce active metabolites. This metabolism is mainly done in the stomach followed by a minor portion of renal and hepatic processing. The major metabolite formed as part of pravastatin metabolism is the 3-alpha-hydroxy isomer. The activity of this metabolite is very clinically negligible. Budesonide is eliminated via Approximately 60% of a budesonide dose is recovered in the urine as the major metabolites 6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone, and their conjugates. No unchanged budesonide is recovered in urine. Pravastatin is eliminated via From the administered dose of pravastatin, about 70% is eliminated in the feces while about 20% is obtained in the urine. When pravastatin is administered intravenously, approximately 47% of the administered dose is eliminated via the urine with 53% of the dose eliminated either via biotransformation of biliary. The half-life of Budesonide is Budesonide has a plasma elimination half life of 2-3. 6h. The terminal elimination half life in asthmatic children 4-6 years old is 2. 3h. The half-life of Pravastatin is The reported elimination half-life of pravastatin is reported to be of 1. 8 hours. The clearance of Budesonide is Budesonide has a plasma clearance of 0. 9-1. 8L/min. The 22R form has a clearance of 1. 4L/min while the 22S form has a clearance of 1. 0L/min. The clearance in asthmatic children 4-6 years old is 0. 5L/min. The clearance of Pravastatin is The reported clearance rate of pravastatin ranges from 6. 3-13. 5 ml. min/kg in adults while in children it has been reported to be of 4-11 L/min. Budesonide toxicity includes Acute overdose of corticosteroids is rare, however prolonged high dosing of corticosteroids can lead to hypercorticism and adrenal axis suppression. In the case of overdose, reduce the dosage of corticosteroids temporarily. A 200mg oral dose is lethal to female mice while a 400mg oral dose is lethal to male mice. Pravastatin toxicity includes The reported oral LD50 of pravastatin in mice is of 8939 mg/kg. There haven't been significant overdosage reports however, in the case of overdosage, symptomatic treatment is recommended along with laboratory monitoring and supportive measures. In carcinogenic studies, high dose administration of pravastatin has been reported to increase the incidence of hepatocellular carcinomas in males and lung carcinomas in females. There is no evidence relating the administration of pravastatin with mutagenicity in different assays not to produce effects in fertility or reproductive potential. Brand names of Budesonide include Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris. Brand names of Pravastatin include No brand names available. No synonyms are available for Budesonide. Budesonide No synonyms are available for Pravastatin. Pravastatin acid Pravastatina Pravastatine Pravastatinum Budesonide summary: It is Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis. Pravastatin summary: It is Pravastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and to reduce the risk of cardiovascular events, including myocardial infarction and stroke. Answer: Bile salt export pump (BSEP/ABCB11) plays a crucial role in the secretion of bile acids from the liver. 1,2,3 For this reason, the concurrent administration of two or more bile salt export pump (BSEP/ABCB11) substrates will compete for the BSEP transporter with bile acids, leading to hepatotoxicity from the accumulation of bile acids or adverse effects from the accumulation of the substrate drugs.

Budesonide

Drug A is Adalimumab. Drug B is Alpelisib. The severity of the interaction is major. The metabolism of Alpelisib can be increased when combined with Adalimumab. The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. Adalimumab is indicated for Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. Alpelisib is indicated for Alpelisib is indicated in combination with fulvestrant to treat postmenopausal women, and men, with advanced or metastatic breast cancer. This cancer must be hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and PIK3CA­ mutated. The cancer must be detected by an FDA-approved test following progression on or after an endocrine-based regimen. Alpelisib is also used to treat adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Adalimumab pharmacodynamics: After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. Alpelisib pharmacodynamics: Alpelisib does not prolong the QTcF interval. Patients taking alpelisib experience a dose dependent benefit from treatment with a 51% advantage of a 200mg daily dose over a 100mg dose and a 22% advantage of 300mg once daily over 150mg twice daily. This suggests patients requiring a lower dose may benefit from twice daily dosing. The mechanism of action of Adalimumab is that it Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). The mechanism of action of Alpelisib is that it Phosphatidylinositol-3-kinase-α (PI3Kα) is responsible for cell proliferation in response to growth factor-tyrosine kinase pathway activation. In some cancers PI3Kα's p110α catalytic subunit is mutated making it hyperactive. Alpelisib inhibits (PI3K), with the highest specificity for PI3Kα. Adalimumab absorption: The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4. 7 ± 1. 6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0. 5 to 10. 0 mg/kg following a single intravenous dose. Alpelisib absorption: Alpelisib reached a peak concentration in plasma of 1320±912ng/mL after 2 hours. Alpelisib has an AUC last of 11,100±3760h ng/mL and an AUC INF of 11,100±3770h ng/mL. A large, high fat meal increases the AUC by 73% and Cmax by 84% while a small, low fat meal increases the AUC by 77% and Cmax by 145%. The volume of distribution of Adalimumab is The distribution volume (Vss) ranged from 4. 7 to 6. 0 L following intravenous administration of doses ranging from 0. 25 to 10 mg/kg in RA patients. The volume of distribution of Alpelisib is The apparent volume of distribution at steady state is 114L. No protein binding information is available for Adalimumab. Alpelisib is Alpelisib is 89% protein bound. bound to plasma proteins. No metabolism information is available for Adalimumab. Alpelisib metabolism: Alpelisib is metabolized by hydrolysis reactions to form the primary metabolite. It is also metabolized by CYP3A4. The full metabolism of Alpelisib has yet to be determined but a series of reactions have been proposed. The main metabolic reaction is the substitution of an amine group on alpelisib for a hydroxyl group to form a metabolite known as M4 or BZG791. Alpelisib can also be glucuronidated to form the M1 and M12 metabolites. Adalimumab is eliminated via Adalimumab is most likely removed by opsonization via the reticuloendothelial system. Alpelisib is eliminated via 36% of an oral dose is eliminated as unchanged drug in the feces and 32% as the primary metabolite BZG791 in the feces. About 2% of an oral dose is eliminated in the urine as unchanged drug and 7. 1% as the primary metabolite BZG791. In total 81% of an oral dose is eliminated in the feces and 14% is eliminated in the urine. The half-life of Adalimumab is The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. The half-life of Alpelisib is The mean half life of alprelisib is 8 to 9 hours. The clearance of Adalimumab is The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0. 25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. The clearance of Alpelisib is The mean apparent oral clearance was 39. 0L/h. The predicted clearance is 9. 2L/hr under fed conditions. Adalimumab toxicity includes Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. Alpelisib toxicity includes Patients experiencing an overdose may present with hyperglycemia, nausea, asthenia, and rash. There is no antidote for an overdose of alpelisib so patients should be treated symptomatically. Data regarding an LD 50 is not readily available. In clinical trials, patients were given doses of up to 450mg once daily. Brand names of Adalimumab include Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry. Brand names of Alpelisib include Piqray 300 Mg Daily Dose, Vijoice 50 Mg 28 Day. No synonyms are available for Adalimumab. No synonyms are available for Alpelisib. Adalimumab summary: It is Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. Alpelisib summary: It is No summary available. Answer: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index.

Adalimumab

Drug A is Obiltoxaximab. Drug B is Alemtuzumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Obiltoxaximab. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Obiltoxaximab is indicated for Investigated for use/treatment in anthrax exposure, bacterial infection, crohn's disease, and graft versus host disease. Alemtuzumab is indicated for LEMTRADA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. LEMTRADA contains the same active ingredient (alemtuzumab) found in CAMPATH, and CAMPATH is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), although generally administered at higher and more frequent doses (e. g., 30 mg) than recommended in the treatment of MS. Obiltoxaximab pharmacodynamics: No pharmacodynamics available. Alemtuzumab pharmacodynamics: Alemtuzumab depletes circulating T and B lymphocytes after each treatment course. In clinical trials, the lowest cell counts occurred 1 month after a course of treatment at the time of the first post-treatment blood count. Lymphocyte counts then increased over time: B cell counts usually recovered within 6 months; T cell counts increased more slowly and usually remained below baseline 12 months after treatment. Approximately 60% of patients had total lymphocyte counts below the lower limit of normal 6 months after each treatment course and 20% had counts below the lower limit of normal after 12 months. Reconstitution of the lymphocyte population varies for the different lymphocyte subtypes. At Month 1 in clinical trials, the mean CD4+ lymphocyte count was 40 cells per microliter, and, at Month 12, 270 cells per microliter. At 30 months, approximately half of patients had CD4+ lymphocyte counts that remained below the lower limit of normal. The mechanism of action of Obiltoxaximab is that it ETI-204 is an affinity-enhanced, de-immunized antibody, which means that its ability to bind to its target pathogen has been strengthened and that elements that might cause an immune response have been removed. ETI-204 targets and binds to Protective Antigen, which prevents the anthrax toxins from binding to and entering the cells in the body, thereby preventing death. The mechanism of action of Alemtuzumab is that it The precise mechanism by which alemtuzumab exerts its therapeutic effects in multiple sclerosis is unknown but is presumed to involve binding to CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes, and macrophages. Following cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis. and complement-mediated lysis. Research suggests that alemtuzumab can also exert immunomodulatory effects through the depletion and repopulation of lymphocytes, including alterations in the number, proportions, and properties of some lymphocyte subsets posttreatment, increasing representation of regulatory T cell subsets, and increasing representation of memory T- and B-lymphocytes. The reduction in the level of circulating B and T cells by alemtuzumab and subsequent repopulation may reduce the potential for relapse, which ultimately delays disease progression. No absorption information is available for Obiltoxaximab. Alemtuzumab absorption: Serum concentrations increased with each consecutive dose within a treatment course, with the highest observed concentrations occurring following the last infusion of a treatment course. The mean maximum concentration was 3014 ng/mL on Day 5 of the first treatment course, and 2276 ng/mL on Day 3 of the second treatment course. No volume of distribution information is available for Obiltoxaximab. The volume of distribution of Alemtuzumab is Alemtuzumab is largely confined to the blood and interstitial space with a central volume of distribution of 14. 1 L. No protein binding information is available for Obiltoxaximab. No protein binding information is available for Alemtuzumab. No metabolism information is available for Obiltoxaximab. No metabolism information is available for Alemtuzumab. Obiltoxaximab is eliminated via No route of elimination available. Alemtuzumab is eliminated via Alemtuzumab is a large-molecule monoclonal antibody and as such, it is cleared primarily through target-mediated clearance and. through simple non-target specific IgG clearance mechanisms. Alemtuzumab is not excreted renally or eliminated via cytochrome P450 (CYP450) isoenzymes. Alemtuzumab is most likely removed by opsonization via the reticuloendothelial system when bound to B or T lymphocytes. The half-life of Obiltoxaximab is No half-life available. The half-life of Alemtuzumab is The elimination half-life was approximately 2 weeks and was comparable between courses. The serum concentrations were generally undetectable (<60 ng/mL) within approximately 30 days following each treatment course. No clearance information is available for Obiltoxaximab. The clearance of Alemtuzumab is Clearance of alemtuzumab ranged from 0. 012 – 0. 096 l/h depending on the study, dose group, and anti-alemtuzumab antibody status. The inter-subject variability for clearance was large (58 %). Higher clearance values were observed in cycle 1 compared to cycle 2, with the decrease in clearance from cycle 1 to cycle 2 being less than 20%. No toxicity information is available for Obiltoxaximab. Alemtuzumab toxicity includes LEMTRADA induces persistent thyroid disorders [see Warnings and Precautions (5. 8)]. Untreated hypothyroidism in pregnant women increases the risk of miscarriage and may have effects on the fetus including mental retardation and dwarfism. In mothers with Graves’ disease, maternal thyroid stimulating hormone receptor antibodies can be transferred to a developing fetus and can cause neonatal Graves’ disease. In a patient who developed Graves’ disease after treatment with alemtuzumab, placental transfer of anti-thyrotropin receptor antibodies resulted in neonatal Graves’ disease with thyroid storm in her infant who was born 1 year after. alemtuzumab dosing. When LEMTRADA was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6-10 or GD 11-15) at doses of 3 or 10 mg/kg IV, no teratogenic effects were observed. However, there was an increase in embryo lethality (increased postimplantation loss and the number of dams with all fetuses dead or resorbed) in pregnant animals dosed during GD 11-15. In a separate study in pregnant huCD52 transgenic mice, administration of LEMTRADA during organogenesis (GD 6-10 or GD 11-15) at doses of 3 or 10 mg/kg IV, decreases in B- and T-lymphocyte populations were observed in the offspring at both doses tested. In pregnant huCD52 transgenic mice administered LEMTRADA at doses of 3 or 10 mg/kg/day IV throughout gestation and lactation, there was an increase in pup deaths during the lactation period at 10 mg/kg. Decreases in T- and B-lymphocyte populations and in antibody response were observed in offspring at both doses tested. Before initiation of LEMTRADA treatment, women of childbearing potential should be counseled on the potential for serious risk to the fetus. To avoid in-utero exposure to LEMTRADA, women of childbearing potential should use effective contraceptive measures when receiving a course of treatment with LEMTRADA and for 4 months following that course of treatment. In huCD52 transgenic mice, administration of LEMTRADA prior to and during the mating period resulted in adverse effects on sperm parameters in males and a reduced number of corpora lutea and implantations in females. Two MS patients experienced serious reactions (headache, rash, and either hypotension or sinus tachycardia) after a single accidental infusion of up to 60 mg of LEMTRADA. Doses of LEMTRADA greater than those recommended may increase the intensity and/or duration of infusion reactions or their immune effects. There is no known antidote for alemtuzumab overdosage. Brand names of Obiltoxaximab include Anthim. Brand names of Alemtuzumab include Campath, Lemtrada, MabCampath. No synonyms are available for Obiltoxaximab. No synonyms are available for Alemtuzumab. Obiltoxaximab summary: It is Obiltoxaximab is a monoclonal antibody used for prophylaxis or treatment of inhalational anthrax. Alemtuzumab summary: It is Alemtuzumab is a monoclonal anti-CD52 antibody used in the treatment of B-cell chronic lymphocytic leukemia and relapsing forms of multiple sclerosis. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Obiltoxaximab

Drug A is Antithymocyte immunoglobulin (rabbit). Drug B is Besilesomab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Besilesomab. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Antithymocyte immunoglobulin (rabbit) is indicated for prevention of renal transplant rejection. Besilesomab is indicated for Besilesomab is radiolabelled with sodium pertechnetate (Tc99m) solution to develop technetium (Tc99m) besilesomab solution. This solution is indicated in adults for scintigraphic imaging - in conjunction with other appropriate imaging modalities, when possible - in determining the location of inflammation/infection in peripheral bone in adults with suspected osteomyelitis. When utilized as such, this medicinal product is for diagnostic use only. Antithymocyte immunoglobulin (rabbit) pharmacodynamics: Antithymocyte Globulin (ATG) is a concentrated anti-human T-lymphocyte immunoglobulin preparation derived from rabbits after immunization with a T-lympoblast cell line. ATG is an immunosuppressive product for the prevention and treatment of acute rejection following organ transplantation. ATG reduces the host immune response against tissue transplants or organ allografts. Besilesomab pharmacodynamics: In a study employing cryo-preserved human tissues using an indirect alkaline phosphatase anti-alkaline phosphatase technique, besilesomab antibody from hybridoma supernatants demonstrated staining to cytoplasmic, membranous, and interstitial areas of primary colon carcinoma tissue, to single granulocytic cells in normal human liver and lung and to a large proportion of granulocytic cells in normal human bone marrow but not to blood vessels or connective tissue. Additionally, the antibody also shows binding to the granulocytic cells of breast, kidney, parotid gland, pituitary, lymph nodes, and spleen tissues, as well as colonic, pancreatic, and some lung and breast carcinomas. The purified besilesomab antibody and the prepared kit subsequently bound similarly to granulocytes in normal bone marrow, lung, liver, spleen, and colorectal carcinomas. Furthermore, the prepared kit also produced some staining in some connective tissue fibres in normal lung, some muscle fibres in normal colon, and in liver parenchymal cells. In general however, besilesomab does not bind significantly to blood vessels and connective tissue. The mechanism of action of Antithymocyte immunoglobulin (rabbit) is that it Binds to multiple, T-cell specific antigens leading to T-lymphocyte cell death via complement mediated cytotoxicity or apoptosis. The mechanism of action of Besilesomab is that it Nonspecific cross-reacting antigens (NCA) is the name of a collection of highly glycosylated bacterial binding receptors expressed on human granulocytes and other tissues. In particular, these glycoprotein receptors are members of the immunoglobulin supergene family and are related structurally to carcinoembryonic antigen (CEA). CEA is found naturally in the human body and its expression may be increased in both cancer and non-cancerous (benign) circumstances. Besilesomab is subsequently a murine immunoglobulin monoclonal antibody of IgG1 isotype designed to recognise and bind specifically to NCA-95, or nonspecific cross-reacting antigen 95, an epitope found expressed on the cell membranes of granulocytes and granulocyte precursors. When radiolabelled with sodium pertechnetate (Tc99m) solution to develop technetium (Tc99m) besilesomab solution, this radiolabelled medicine is injected into patients where the monoclonal antibody carries it to target CEA on target granulocytes. When large numbers of CEA expressing granulocytes gather to the site of an infection, the radioactive monoclonal antibodies will also accumulate at such sites, where it can be detected by diagnostic scanning. The resultant images show where the radioactive besilesomab has accumulated, locating areas affected by osteomyelitis, infection, or inflammation. Furthermore, it is believed that the besilesomab accumulation is predominantly passive (via increased vascular permeability) and only partially active (via migration of human granulocytes carrying besilesomab to the infection/inflammation location) since only 10% to 20% of the injected radio-diagnostic agent binds in vivo to human circulating granulocytes. Specific binding of besilesomab to activated granulocytes that have already migrated to sites of infection/inflammation might be the primary part of the detection signal. Antithymocyte immunoglobulin (rabbit) absorption: T-cell depletion usually observed within 1 day after initiating therapy. Average 21. 5 and 87 mcg/mL 4–8 hours post-infusion after first and last IV doses, respectively, when given for 7–11 days. Besilesomab absorption: As the diagnostic agent is administered intravenously, it is expected that the bioavailability is 100%. Approximately six hours after injection, about 1. 5% of the whole body radioactivity is detected in the liver while about 3. 0% is found in the spleen. Observations twenty-four hours after injection demonstrate percentages of radioactivity of 1. 6% in the liver and 2. 3% in the spleen. However, non pathological, unusual accumulations of the radioactive agent can be detected in the spleen (up to 6% of patients), in the bowel (up to 4% of patients), in the liver and bone marrow (up to 3% of patients), and in the thyroid and kidneys (up to 2% of patients). No volume of distribution information is available for Antithymocyte immunoglobulin (rabbit). The volume of distribution of Besilesomab is In the besilesomab clinical trial Study 7D-101SZ-A, volumes of distribution were determined as approximately 4L - which was close to the plasma volume - in the central compartment, whether calculated from plasma radioactivity or from intact monoclonal antibody concentrations; the peripheral compartment was somewhat greater, at about 6L for both methods. No protein binding information is available for Antithymocyte immunoglobulin (rabbit). Besilesomab is Studies demonstrate that prepared kit besilesomab binds up to 97. 45% and 96. 58% of peripheral blood granulocytes in males and females respectively and less than 5% of other peripheral blood cells. Moreover, no significant binding of the antibody to other human peripheral blood cells like erythrocytes, platelets, lymphocytes, and monocytes was observed. As well, besilesomab demonstrates no cross-reactivity with human platelets. bound to plasma proteins. Antithymocyte immunoglobulin (rabbit) metabolism: Most likely removed by opsonization via the reticuloendothelial system when bound to T lymphocytes, or by human antimurine antibody production. Besilesomab metabolism: The besilesomab antibody is mainly metabolized via hepatic clearance into amino acids. Nevertheless, liver uptake of radioactivity was observed to be minimal under trial conditions and liver impairment is considered unlikely to affect besilesomab metabolism and elimination in any clinically significant manner. The total blood radioactivity occurring from the administration of besilesomab is generally the result of the contribution of radioactive intact labelled antibody and other radioactive moieties like metabolized antibody fragments, smaller radiometabolites, and free technetium (Tc99m). Antithymocyte immunoglobulin (rabbit) is eliminated via No route of elimination available. Besilesomab is eliminated via Measurement of radioactivity levels in urine shows that up to 14% of the administered activity is excreted via the bladder during the 24 h post-injection period. Low renal clearance activity (of 0. 2 L/h for a glomerular filtration rate of approximately 7 L/h) also suggests that the kidney is not the primary route of besilesomab elimination. Additionally, over 30 hours rat pharmacokinetic studies also similarly demonstrated that 31-34% of the radioactivity was excreted in the urine and only 7-13% in the faeces. The faecal elimination was observed primarily from the 17h time period onward. Furthermore, while radioactivity associated with intact antibody tends to stay in the vascular compartment for a long time, metabolized radioactive fragments, small radio-metabolites, and free pertechnetate (Tc99m) clears quickly from blood and will accumulate in the kidneys and further in the urine. In all besilesomab studies to date, approximately 14% of the injected radioactivity was recovered in the urine, which was only collected for 24 hours after administration. The half-life of Antithymocyte immunoglobulin (rabbit) is 2-3 days, may increase after multiple doses administration. The half-life of Besilesomab is Whole blood concentration-time radioactivity curves show a two-phase course, which can be subdivided into an early phase (0-2 h) and a late phase (5-24 h). After correcting for the decay of radionuclide, the calculated half-life of the early phase is approximately 0. 5 h while the late phase demonstrates a calculated half-life of 16 h. The terminal half-life in man is estimated to be approximately 23 h. No clearance information is available for Antithymocyte immunoglobulin (rabbit). The clearance of Besilesomab is Once administered into the body, prepared technetium (Tc99m) besilesomab can be metabolized into free amino acids, smaller radioactive fragments, or even free pertechnetate (Tc99m). The besilesomab clinical study 7D-101SZ-A consequently reports separate estimated clearance rates of 0. 322 L/h and 0. 242 L/h that were calculated using monitored plasma radioactivity and from monitored intact monoclonal antibody concentrations, respectively. Antithymocyte immunoglobulin (rabbit) toxicity includes Not known whether ATG (rabbit) distributes into human milk; however, other immunoglobulins are distributed into human milk. Besilesomab toxicity includes The most commonly reported adverse reaction associated with the use of besilesomab is the development of Human Anti-Mouse Antibodies (HAMA) after a single administration. Patients who have developed HAMA may potentially have a higher risk for hypersensitivity reactions. Screening for possible previous exposure to murine monoclonal antibodies and tests for the presence of HAMA in prospective patients should be made prior to administrating besilesomab. Moreover, because the incidence of developing HAMA appears to be dose related with besilesomab, the recommended dosage is restricted to no more than 250 micrograms of antibody per injection. Patients who are HAMA positive are consequently contraindicated from using besilesomab. Hypersensitivity to besilesomab or to any other murine antibodies or to any of the excipients associated with the active besilesomab radio-diagnostic agent is subsequently a contraindication. Some patients have also reported hypotension as a common adverse reaction. As exposure to ionizing radiation is linked with cancer induction and a potential for developing hereditary defects, the use of radio-diagnostic besilesomab in pregnant women is considered a formal contraindication. If in doubt about a woman's potential pregnancy, alternative techniques to not using ionizing radiation should be considered and/or offered instead to the patient. Moreover, although it is not known if besilesomab is excreted in human milk, the potential risk to a breast-fed child cannot be excluded. Furthermore, while consideration should be given to the possibility of perhaps delaying the administration of radionuclide agents until the mother has ceased breastfeeding or perhaps certainly choosing alternative radoopharmaceuticals with more appropriate secretion activity, if the use of besilesomab is absolutely necessary then the mother's breastfeeding should be stopped for three days and any expressed feeds during that time discarded. The time period of three days corresponds to 10 half-lives of technetium (Tc99m)(60 hours). At that time, the remaining activity represents about 1/1000 of the initial activity in the body. In general, close contact with infants and pregnant women should be restricted for patients who have been administered besilesomab during the first 12 hours after the injection. Since besilesomab contains sorbitol, patients having any rare hereditary conditions of fructose intolerance should not be administered this medicine. Because no sufficient data regarding the safety and efficacy of using besilesomab in children below the age of 18 years exists, the use of besilesomab in this patient population is not recommended. Even though data regarding the repeated dosing of besilesomab is extremely limited, the use of besilesomab should only be used once in a patient's lifetime. Other medicines that can inhibit inflammation or affect the hematopoietic system (like antibiotics and corticosteroids) can lead to false negative results. Such agents should therefore not be administered together with, or a short time before the injection of besilesomab. Preclinical data obtained with the non-radioactive compound revealed no special hazard for humans based on conventional studies of safety pharmacology, single-dose and repeated dose toxicity, although antimurine antibodies were found in all dose groups (including controls) in a repeated-dose study in monkeys. Genotoxicity studies conducted to test for potentially genotoxic impurities were also negative. Long-term carcinogenicity studies and toxicity to reproduction have not yet been carried out. Brand names of Antithymocyte immunoglobulin (rabbit) include No brand names available. Brand names of Besilesomab include No brand names available. No synonyms are available for Antithymocyte immunoglobulin (rabbit). No synonyms are available for Besilesomab. Antithymocyte immunoglobulin (rabbit) summary: It is Antithymocyte immunoglobulin (rabbit) is a purified form of rabbit anti-thymocyte antibodies used for immunosuppression in patients receiving kidney transplants. Besilesomab summary: It is Besilesomab is a monoclonal antibody bound to technetium-99 used to find infection and inflammation in patients with suspected osteomyelitis. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Antithymocyte immunoglobulin (rabbit)

Drug A is Bromotheophylline. Drug B is Tamsulosin. The severity of the interaction is moderate. Bromotheophylline may increase the excretion rate of Tamsulosin which could result in a lower serum level and potentially a reduction in efficacy. The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response. Bromotheophylline is indicated for Bromotheophylline is used as a diuretic and also, in combination with Acetaminophen, it is used for the relief of temporary water weight gain, bloating, swelling and full feeling associated with the premenstrual and menstrual periods. Tamsulosin is indicated for Tamsulosin is indicated for the treatment of signs and symptoms of benign prostatic hyperplasia. Tamsulosin is also used off label for the treatment of ureteral stones, prostatitis, and female voiding dysfunction. Bromotheophylline pharmacodynamics: Bromotheophylline diuretic action will produce an immediate increase in urination frequency. This effect aids in the relief of bloating and menstrual pain. This diuretic function is performed by the an increase in glomerular filtration and a potential effect in the tubular reabsorption as it is established that the administration of these agents produce a rise in the urinary concentration of sodium a chloride and thus, an increase in their rates of excretion. Tamsulosin pharmacodynamics: Tamsulosin is an alpha adrenoceptor blocker with specificity for the alpha-1A and alpha-1D subtypes, which are more common in the prostate and submaxillary tissue. The final subtype, alpha-1B, are most common in the aorta and spleen. Tamsulosin binds to alpha-1A receptors 3. 9-38 times more selectively than alpha-1B and 3-20 times more selectively than alpha-1D. This selectivity allows for a significant effect on urinary flow with a reduced incidence of adverse reactions like orthostatic hypotension. The mechanism of action of Bromotheophylline is that it Bromotheophylline is part of the group of the xanthines. As part of this group, it is thought that bromotheophylline increases the permeability of the renal tubule, increases glomerular filtration rate and inhibits the sodium reabsorption in the proximal tubule. It is thought but not confirmed that pamabrom as a mixture seems to have an additional mechanism of action in which the presence of 2-amino-2-methyl-1-propanol produces the suppression of the antidiuretic hormone in the posterior pituitary gland. The mechanism of action of Tamsulosin is that it Tamsulosin is a blocker of alpha-1A and alpha-1D adrenoceptors. About 70% of the alpha-1 adrenoceptors in the prostate are of the alpha-1A subtype. By blocking these adrenoceptors, smooth muscle in the prostate is relaxed and urinary flow is improved. The blocking of alpha-1D adrenoceptors relaxes the detrusor muscles of the bladder which prevents storage symptoms. The specificity of tamsulosin focuses the effects to the target area while minimizing effects in other areas. Bromotheophylline absorption: When administered after one single oral dosage, bromotheophylline is rapidly absorbed and it reaches a maximal plasma concentration of 2. 5 mg/L in 0. 78 hours. The mean residence time is registered to be of 12 hours with an AUC in the first 8 hours of 27 mg. h/L. Tamsulosin absorption: Oral tamsulosin is 90% absorbed in fasted patients. The area under the curve is 151-199ng/mL*hr for a 0. 4mg oral dose and 440-557ng/mL*hr for a 0. 8mg oral dose. The maximum plasma concentration is 3. 1-5. 3ng/mL for a 0. 4mg oral dose and 2. 5-3. 6ng/mL for a 0. 8mg oral dose. Taking tamsulosin with food increases the time to maximum concentration from 4-5 hours to 6-7 hours but increases bioavailability by 30% and maximum plasma concentration by 40-70%. The volume of distribution of Bromotheophylline is This pharmacokinetic property has not been determined. The volume of distribution of Tamsulosin is 16L after intravenous administration. Bromotheophylline is This pharmacokinetic property has not been determined. bound to plasma proteins. Tamsulosin is Tamsulosin is 94%-99% protein bound, mostly to alpha-1-acid glycoprotein. bound to plasma proteins. Bromotheophylline metabolism: This pharmacokinetic property has not been determined. Tamsulosin metabolism: Tamsulosin is mostly metabolized in the liver by cytochrome P450 (CYP) 3A4 and 2D6, with some metabolism by other CYPs. CYP3A4 is responsible for the deethylation of tamsulosin to the M-1 metabolite and the oxidative deamination to the AM-1 metabolite, while CYP2D6 is responsible for the hydroxylation of tamsulosin to the M-3 metabolite and the demethylation of tamsulosin to the M-4 metabolite. In addition, tamsulosin can be hydroxylated at a different position by an unknown enzyme to form the M-2 metabolite. The M-1, M-2, M-3, and M-4 metabolites can be glucuronidated, and the M-1 and M-3 metabolites can undergo sulfate conjugation to form other metabolites before excretion. Bromotheophylline is eliminated via This pharmacokinetic property has not been determined. Tamsulosin is eliminated via 97% of an orally administered does is recovered in studies, which 76% in the urine and 21% in the feces after 168 hours. 8. 7% of the dose is excreted as unmetabolized tamsulosin. The half-life of Bromotheophylline is The apparent elimination half-life is registered to be 21. 35 hours. The half-life of Tamsulosin is The half life in fasted patients is 14. 9±3. 9 hours. The elimination half life is 5-7 hours and the apparent half life is 9 to 13 hours in healthy subjects. In patients who require tamsulosin, the apparent half life is 14-15 hours. The clearance of Bromotheophylline is This pharmacokinetic property has not been determined. The clearance of Tamsulosin is 2. 88L/h. Bromotheophylline toxicity includes In overdose, bromotheophylline does not produce hepatic toxicity. Tamsulosin toxicity includes In the event of overdose, patients may experience hypotension and should lie down in a supine position to maintain blood pressure and heart rate. If further measures are required intravenous fluids should be considered. If further progression is required, vasopressors may be used and renal function should be monitored. Dialysis is unlikely to assist in treating overdose because tamsulosin is extensively protein bound. The oral LD50 in rats is 650mg/kg. Tamsulosin is not indicated for use in women and no studies have been performed in pregnancy, though animal studies have not shown fetal harm. Tamsulosin is excreted in the milk of rats but there is no available data on what the effect of this tamsulosin exposure may be. Animal studies have shown male and female rat fertility is affected by tamsulosin due to impairment of ejaculation and fertilization. In men, tamsulosin is associated with abnormal ejaculation. Tamsulosin is not mutagenic but may be carcinogenic at levels above the maximum recommended human dose. Female rats experience a slight increase in the rates of mammary gland fibroadenomas and adenocarcinomas. Brand names of Bromotheophylline include Pamprin Multi-symptom, Premsyn Pms. Brand names of Tamsulosin include Flomax, Jalyn. No synonyms are available for Bromotheophylline. No synonyms are available for Tamsulosin. Tamsulosina Tamsulosine Tamsulosinum Bromotheophylline summary: It is No summary available. Tamsulosin summary: It is Tamsulosin is an alpha-1A and alpha-1B adrenergic receptor antagonist used to treat benign prostatic hyperplasia, ureteral stones, prostatitis, and female voiding dysfunction. Answer: The subject drug induces diuresis1,2, which can theoretically increase the excretion rate of the affected drug, which is eliminated by the kidneys. Additionally, it could affect renal tubular reabsorption of certain drugs. Exposure to the affected drug can be markedly reduced, leading to subtherapeutic drug levels that are unlikely to elicit an adequate clinical response.

Bromotheophylline

Drug A is Buprenorphine. Drug B is Glycerol phenylbutyrate. The severity of the interaction is major. The metabolism of Buprenorphine can be decreased when combined with Glycerol phenylbutyrate. The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects. Buprenorphine is indicated for Buprenorphine is available in different formulations, such as sublingual tablets, buccal films, transdermal films, and injections, alone or in combination with naloxone. The buccal film, intramuscular or intravenous injection, and transdermal formulation are indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. The extended-release subcutaneous injections of buprenorphine are indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. Injections are part of a complete treatment plan that includes counselling and psychosocial support. Sublingual tablets and buccal films, in combination with naloxone, are indicated for the maintenance treatment of opioid dependence as part of a complete treatment plan that includes counselling and psychosocial support. Glycerol phenylbutyrate is indicated for Glycerol phenylbutyrate is a nitrogen-binding agent for the chronic management of adult and pediatric patients ≥2 years of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Buprenorphine pharmacodynamics: Buprenorphine interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, buprenorphine exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Buprenorphine depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Dependence Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. [F4718] Withdrawal Abrupt discontinuation of treatment is not recommended as it may result in an opioid withdrawal syndrome that may be delayed in onset. Signs and symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. [F4718] Risk of Respiratory and Central Nervous System (CNS) Depression and Overdose Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant, including alcohol. Use buprenorphine and naloxone sublingual tablets with caution in patients with compromised respiratory function (e. g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression). Risk of Overdose in Opioid Naïve Patients There have been reported deaths of opioid-naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine and naloxone sublingual tablets are not appropriate as an analgesic in opioid-naïve patients. Precipitation of Opioid Withdrawal Signs and Symptoms If buprenorphine is started in opioid-dependent individuals, it will displace the other opioids and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms. Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Because it contains naloxone, buprenorphine and naloxone sublingual tablets are also highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Gastrointestinal Effects Buprenorphine and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and should be administered with caution to patients with dysfunction of the biliary tract. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Use in Patients With Impaired Hepatic Function Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. The doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. However, buprenorphine/naloxone products are not recommended for initiation of (treatment induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy. Risk of Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, buprenorphine and naloxone sublingual tablets may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated. Orthostatic Hypotension Like other opioids, buprenorphine and naloxone sublingual tablets may produce orthostatic hypotension in ambulatory patients. Elevation of Cerebrospinal Fluid Pressure Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation. Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract. Glycerol phenylbutyrate pharmacodynamics: Glycerol phenylbutyrate prolongs the QTc interval. The mechanism of action of Buprenorphine is that it Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. It demonstrates a high affinity for the mu-opioid receptor but has lower intrinsic activity compared to other full mu-opioid agonists such as heroin, oxycodone, or methadone. This means that buprenorphine preferentially binds the opioid receptor and displaces lower affinity opioids without activating the receptor to a comparable degree. Clinically, this results in a slow onset of action and a clinical phenomenon known as the "ceiling effect" where once a certain dose is reached buprenorphine's effects plateau. This effect can be beneficial, however, as dose-related side effects such as respiratory depression, sedation, and intoxication also plateau at around 32mg, resulting in a lower risk of overdose compared to methadone and other full agonist opioids. It also means that opioid-dependent patients do not experience sedation or euphoria at the same rate that they might experience with more potent opioids, improving quality of life for patients with severe pain and reducing the reinforcing effects of opioids which can lead to drug-seeking behaviours. Buprenorphine's high affinity, but low intrinsic activity for the mu-opioid receptor also means that if it is started in opioid-dependent individuals, it will displace the other opioids without creating an equal opioid effect and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms (i. e. anxiety, restlessness, gastrointestinal distress, diaphoresis, intense drug cravings, and tachycardia). Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Buprenorphine is commercially available as the brand name product Suboxone which is formulated in a 4:1 fixed-dose combination product along with naloxone, a non-selective competitive opioid receptor antagonist. Combination of an opioid agonist with an opioid antagonist may seem counterintuitive, however this combination with naloxone is intended to reduce the abuse potential of Suboxone, as naloxone is poorly absorbed by the oral route (and has no effect when taken orally), but would reverse the opioid agonist effects of buprenorphine if injected intravenously. The mechanism of action of Glycerol phenylbutyrate is that it The toxic accumulation of ammonia in the blood and brain arise from urea cycle disorders in which patients are deficient in critical enzymes or transporters that are involved in the synthesis of urea from ammonia. Glycerol phenylbutyrate is a prodrug - the major metabolite, phenylacetate (PAA) is the molecule that binds to nitrogen. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form phenylacetylglutamine (PAGN), which is excreted by the kidneys. PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion. Buprenorphine absorption: Bioavailablity of buprenorphine/naloxone is very high following intravenous or subcutaneous administration, lower by the sublingual or buccal route, and very low when administered by the oral route. It is therefore provided as a sublingual tablet that is absorbed from the oral mucosa directly into systemic circulation. Clinical pharmacokinetic studies found that there was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional. Buprenorphine combination with naloxone (2mg/0. 5mg) provided in sublingual tablets demonstrated a Cmax of 0. 780 ng/mL with a Tmax of 1. 50 hr and AUC of 7. 651 ng. hr/mL. Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine. Glycerol phenylbutyrate absorption: Glycerol phenylbutyrate is a prodrug in which phenylbutyrate (PBA) is released from the glycerol backbone by lipases in the gastrointestinal tract. PBA then undergoes beta-oxidtion to form PAA. When a single oral dose of 2. 9 mL/m2 of Glycerol phenylbutyrate is given to fasting adult subjects, the pharmacokinetic parameters are as follows:. Tmax is PBA = 2 hours; PAA = 4 hours; PAGN = 4 hours. Cmax is PBA = 37. 0 µg/mL; PAA = 14. 9 µg/mL; PAGN = 30. 2 µg/mL. In healthy subjects, the hydrolysis of glycerol phenylbutyrate is incomplete, but to what extent is unknown. When glycerol phenylbutyrate is given to adult UCD patients, maximum plasma concentrations at steady state (Cmaxss) of PBA, PAA, and PAGN occurred at 8 h, 12 h, and 10 h, respectively, after the first dose in the day. Intact glycerol phenylbutyrate was not detectable in plasma in UCD patients. The volume of distribution of Buprenorphine is Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. It is able to cross into the placenta and breast milk. No volume of distribution information is available for Glycerol phenylbutyrate. Buprenorphine is Buprenorphine is approximately 96% protein-bound, primarily to alpha- and beta-globulin. bound to plasma proteins. Glycerol phenylbutyrate is PBA = 80. 6% to 98. 0%; bound to plasma proteins. PAA = 37. 1% to 65. 6%; PAGN = 7% to 12%. Buprenorphine metabolism: Buprenorphine is metabolized to norbuprenorphine via Cytochrome P450 3A4/3A5-mediated N-dealkylation. Buprenorphine and norbuprenorphine both also undergo glucuronidation to the inactive metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, respectively. While norbuprenorphine has been found to bind to opioid receptors in-vitro, brain concentrations are very low which suggests that it does not contribute to the clinical effects of buprenorphine. Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group. Glycerol phenylbutyrate metabolism: Pancreatic lipases hydrolyze glycerol phenylbutyrate to release PBA from the glycerol backbone. PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN. Buprenorphine is eliminated via Buprenorphine, like morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine). The overall mean elimination half-life of buprenorphine in plasma ranges from 31 to 42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter. Glycerol phenylbutyrate is eliminated via Glycerol phenylbutyrate is mainly excreted as PAGN in the urine (68. 9% in adults and 66. 5% in pediatric UCD patients). PAA and PBA represented minor urinary metabolites, each accounting for <1% of the administered dose of PBA. The half-life of Buprenorphine is Buprenorphine demonstrates slow dissociation kinetics (~166 min), which contributes to its long duration of action and allows for once-daily or even every-second-day dosing. In clinical trial studies, the half-life of sublingually administered buprenorphine/naloxone 2mg/0. 5mg was found to be 30. 75 hours. The half-life of Glycerol phenylbutyrate is No half-life available. The clearance of Buprenorphine is Clearance may be higher in children than in adults. Plasma clearance rate, IV administration, anaesthetized patients = 901. 2 ± 39. 7 mL/min; Plasma clearance rate, IV administration, healthy subjects = 1042 - 1280 mL/min. No clearance information is available for Glycerol phenylbutyrate. Buprenorphine toxicity includes Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression and death. Glycerol phenylbutyrate toxicity includes Most common adverse reactions in ≥10% of patients are diarrhea, flatulence, and headache. Brand names of Buprenorphine include Belbuca, Brixadi, Buprenex, Buprenorphine, Butrans, Sublocade, Suboxone, Subutex, Zubsolv. Brand names of Glycerol phenylbutyrate include Ravicti. No synonyms are available for Buprenorphine. Buprenorfina Buprenorphine Buprenorphinum No synonyms are available for Glycerol phenylbutyrate. GT4P Buprenorphine summary: It is Buprenorphine is a partial opioid agonist used for management of severe pain that is not responsive to alternative treatments. Also used for maintenance treatment of opioid addiction. Glycerol phenylbutyrate summary: It is Glycerol phenylbutyrate is a nitrogen-binding agent used to manage patients with urea cycle disorders who cannot be sufficiently managed amino acid supplementation and/or dietary restrictions. Answer: The subject drug is a strong CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, which could increase serum concentrations as well as the risk and severity of adverse effects.

Buprenorphine

Drug A is Oxytocin. Drug B is Solifenacin. The severity of the interaction is minor. The risk or severity of QTc prolongation can be increased when Oxytocin is combined with Solifenacin. Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females. Oxytocin is indicated for Administration of exogenous oxytocin is indicated in the antepartum period to initiate or improve uterine contractions for vaginal delivery in situations where there is fetal or maternal concern. For example, It may be used to induce labor in cases of Rh sensitization, maternal diabetes, preeclampsia at or near term, and when delivery is indicated due to prematurely ruptured membranes. Importantly, oxytocin is not approved or indicated for elective induction of labor. Oxytocin may be used to reinforce labor in select cases of uterine inertia and as adjunctive therapy in the management of incomplete or inevitable abortion. In the postpartum period, oxytocin may be used to induced contractions in the 3rd stage of labor and to control postpartum bleeding or hemorrhage. Solifenacin is indicated for Solifenacin tablets are indicated to treat an overactive bladder with urinary incontinence, urgency, and frequency. Oxytocin pharmacodynamics: Oxytocin is a nonapeptide, pleiotropic hormone that exerts important physiological effects. It is most well known to stimulate parturition and lactation, but also has important physiological influences on metabolic and cardiovascular functions, sexual and maternal behaviour, pair bonding, social cognition, and fear conditioning. It is worth noting that oxytocin receptors are not limited to the reproductive system but can be found in many peripheral tissues and in central nervous system structures including the brain stem and amygdala. Solifenacin pharmacodynamics: Solifenacin antagonizes the M2 and M3 muscarinic receptors in the bladder to treat an overactive bladder. It has a long duration of action as it is usually taken once daily. Patients taking solifenacin should be aware of the risks of angioedema and anaphylaxis. The mechanism of action of Oxytocin is that it Oxytocin plays a vital role in labour and delivery. The hormone is produced in the hypothalamus and is secreted from the paraventricular nucleus to the posterior pituitary where it is stored. It is then released in pulses during childbirth to induce uterine contractions. The concentration of oxytocin receptors on the myometrium increases significantly during pregnancy and reaches a peak in early labor. Activation of oxytocin receptors on the myometrium triggers a downstream cascade that leads to increased intracellular calcium in uterine myofibrils which strengthens and increases the frequency of uterine contractions. In humans, most hormones are regulated by negative feedback; however, oxytocin is one of the few that is regulated by positive feedback. The head of the fetus pushing on the cervix signals the release of oxytocin from the posterior pituitary of the mother. Oxytocin then travels to the uterus where it stimulates uterine contractions. The elicited uterine contractions will then stimulate the release of increasing amounts of oxytocin. This positive feedback loop will continue until parturition. Since exogenously administered and endogenously secreted oxytocin result in the same effects on the female reproductive system, synthetic oxytocin may be used in specific instances during the antepartum and postpartum period to induce or improve uterine contractions. The mechanism of action of Solifenacin is that it Solifenacin is a competitive muscarinic receptor antagonist. It has the highest affinity for M3, M1, and M2 muscarinic receptors. 80% of the muscarinic receptors in the bladder are M2, while 20% are M3. Solifenacin's antagonism of the M3 receptor prevents contraction of the detrusor muscle, while antagonism of the M2 receptor may prevent contraction of smooth muscle in the bladder. Oxytocin absorption: Oxytocin is administered parenterally and is fully bioavailable. It takes approximately 40 minutes for oxytocin to reach steady-state concentrations in the plasma after parenteral administration. Solifenacin absorption: Solifenacin is well absorbed in the duodenum, jejunum, and ileum but not the stomach. Absorption occurs via passive diffusion and so no transporters are involved. The mean oral bioavailability of solifenacin is 88%. The Tmax of solifenacin is 3-8 hours with a C ss of 32. 3ng/mL for a 5mg oral dose and 62. 9ng/mL for a 10mg oral dose. No volume of distribution information is available for Oxytocin. The volume of distribution of Solifenacin is The volume of distribution of solifenacin is 600L. No protein binding information is available for Oxytocin. Solifenacin is Solifenacin is 93-96% protein bound in plasma, mainly to alpha-1-acid glycoprotein. bound to plasma proteins. Oxytocin metabolism: Oxytocin is rapidly removed from the plasma by the liver and kidney. The enzyme oxytocinase is largely responsible for the metabolism and regulation of oxytocin levels in pregnancy and only a small percentage of the neurohormone is excreted in the urine unchanged. Oxytocinase activity increases throughout pregnancy and peaks in the plasma, placenta and uterus near term. The placenta is a key source of oxytocinase during gestation and produces increasing amounts of the enzyme in response to increasing levels of oxytocin produced by the mother. Oxytocinase activity is also expressed in mammary glands, heart, kidney, and the small intestine. Lower levels of activity can be found in the brain, spleen, liver, skeletal muscle, testes, and colon. The level of oxytocin degradation is negligible in non-pregnant women, men, and cord blood. Solifenacin metabolism: Solifenacin undergoes N-oxidation at the quinuclidin ring by cytochrome P450, though the exact enzymes are not revealed in the literature. The tetrahydroisoquinolone ring is 4R-hydroxylated by CYP3A4, CYP1A1, and CYP2D6. A 4R-hydroxy N-oxide metabolite is also formed by CYP3A4. Finally, solifenacin can undergo direct glucuronidation. Only solifenacin and the 4R-hydroxy metabolite are pharmacologically active. Oxytocin is eliminated via The enzyme oxytocinase is largely responsible for the metabolism and regulation of oxytocin levels in pregnancy; only a small percentage of the neurohormone is excreted in the urine unchanged. Solifenacin is eliminated via 69. 2±7. 8% of a radiolabelled dose is recovered in the urine, 22. 5±3. 3% was recovered in feces, and 0. 4±7. 8% was recovered in exhaled air. 18% of solifenacin is eliminated as the N-oxide metabolite, 9% is eliminated as the 4R-hydroxy N-oxide metabolite, and 8% is eliminated as the 4R-hydroxy metabolite. The half-life of Oxytocin is The plasma half-life of oxytocin ranges from 1-6 minutes. The half-life is decreased in late pregnancy and during lactation. The half-life of Solifenacin is The elimination half life of solifenacin ranges from 33-85 hours. The clearance of Oxytocin is In a study that observed 10 women who were given oxytocin to induce labor, the mean metabolic clearance rate was 7. 87 mL/min. The clearance of Solifenacin is The clearance of solifenacin is 7-14L/h and a renal clearance of 0. 67-1. 51L/h. Oxytocin toxicity includes Administration of supratherapeutic doses of exogenous oxytocin can lead to myocardial ischemia, tachycardia, and arrhythmias. High doses can also lead to uterine spasms, hypertonicity, or rupture. Oxytocin has antidiuretic properties, thus, high daily doses (as a single dose or administered slowly over 24 hours) may lead to extreme water intoxication resulting in maternal seizures, coma, and even death. The risk of antidiuresis and water intoxication in the mother appears to be greater when fluids are given orally. Solifenacin toxicity includes The LD 50 of Solifenacin has yet to be determined. Signs of overdose include severe anticholinergic effects, mental status changes, and decreased consciousness. In case of overdose, treat patients with gastric lavage and supportive measures. Monitor patients with an ECG. Brand names of Oxytocin include Pitocin. Brand names of Solifenacin include Vesicare. No synonyms are available for Oxytocin. No synonyms are available for Solifenacin. Oxytocin summary: It is Oxytocin is a recombinant hormone used to induce or strengthen uterine contractions in pregnant women to aid in labor and delivery or to control postpartum bleeding. Solifenacin summary: It is Solifenacin is a muscarinic antagonist with antispasmodic properties used to treat urge urinary incontinence, urgency, and urinary frequency associated with an overactive bladder. Answer: Both the subject and affected drug have the potential to cause prolongation of the cardiac QTc interval. Concurrent use of multiple QTc-prolonging medications may result in an additive effect on the QTc interval, enhancing prolongation and increasing the risk of sudden cardiac death due to Torsades de Pointes (TdP), a type of ventricular tachycardia. The risk of developing TdP is also increased by a number of patient-specific factors, such as advanced age, female gender, hypokalemia, hypomagnesemia, hypocalcemia, and concomitant diuretic use, amongst others. There are discrepancies in regards to how QTc interval prolongation should be defined, but a commonly accepted definition is an absolute QTc value of ≥470ms in males and ≥480ms in females.

Oxytocin

Drug A is Coagulation factor X human. Drug B is Tinzaparin. The severity of the interaction is major. The therapeutic efficacy of Coagulation factor X human can be decreased when used in combination with Tinzaparin. Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. Coagulation factor X human is indicated for The human coagulation factor X is indicated in adults and children with hereditary Factor X deficiency for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, and perioperative management of bleeding in patients with mild and moderate hereditary Factor X deficiency. It is also indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA, e. g., warfarin) therapy in adult patients with acute major bleeding. Tinzaparin is indicated for Tinzaparin is used for the prevention of postoperative venous thromboembolism in patients undergoing orthopedic surgery and in patients undergoing general surgery who are at high risk of developing postoperative venous thromboembolism. It is also used for the treatment of deep vein thrombosis and/or pulmonary embolism. It is indicated for use in preventing clot formation in indwelling intravenous lines for hemodialysis. Coagulation factor X human pharmacodynamics: Clinical human coagulation Factor X solution increases plasma levels of Factor X and can temporarily correct the coagulation defect in these patients, as reflected by decrease in the activated Partial Thromboplastin Time (aPTT) and prothrombin time (PT). Tinzaparin pharmacodynamics: Tinzaparin, like other LMWHs, have a higher anti-Xa activity than anti-IIa activity. The anti-Xa activity of tinzaparin is 2. 0 +/- 0. 5 times greater than its to anti-IIa activity. Heparin exhibits approximately equal inhibitory activity against Xa and IIa. Tinzaparin is an anticoagulant that blocks the formation of thrombi. Like all LMWHs, tinzaparin only causes activated partial thromboplastin time (aPTT) prolongation at higher doses and routine monitoring is not recommended. However, anti-factor Xa levels may be monitored in some conditions such as pregnancy and renal dysfunction. Its use should be avoided in patients with a creatinine clearance less than 20 mL/min. In these patients, unfractionated heparin should be used. Tinzaparin can be used in patients who have a creatinine clearance between 20-30 mL/min, giving it the highest safety threshold for use in renal failure patients compared to all the LMWHs. The mechanism of action of Coagulation factor X human is that it Factor X is an inactive zymogen that is synthesized in the liver, which can be activated by Factor IXa (via the intrinsic pathway) or by Factor VIIa (via the extrinsic pathway). It is composed of a light chain which contains the Gla (glutamic acid) domain and two epidermal growth factor domains, and a heavy chain that contains the catalytic serine protease domain. The conversion of inactive Factor X into the active form Factor Xa requires the cleavage of a 52-residue peptide from the heavy chain and the release of 52-residue activation peptide that contains the His236, Asp228 and Ser379 catalytic site. This activation step can occur through the extrinsic or intrinsic pathway and is considered to be the first step in the common pathway to fibrin formation. Factor Xa plays a critical initiation step of the coagulation pathway by cleaving and activating prothrombin to thrombin in complex with FVa, Ca2+ and phospholipids. This complex is also known as the prothrombinase complex. Thrombin then acts upon soluble fibrinogen and Factor XIII to generate a cross-linked fibrin clot. The mechanism of action of Tinzaparin is that it Tinzaparin binds to the plasma protein antithrombin III, forming a complex with then accelerates the inhibition of factor Xa. Its affinity for factor Xa is 2-4 times greater than that of unbound ATIII. The inactivation of factor Xa in turn will exponentially generation of thrombin (factor IIa) molecules, which is needed to activate fibrinogen to fibrin. The coagulation cascade is inhibited because fibrin cannot be formed in the presence of tinzaparin. Like all LMWH, it cannot be given intramuscularly due to increased risk of hematoma. Coagulation factor X human absorption: Following a single intravenous dose of 25 IU/kg, the mean peak plasma concentration (CV%) was 0. 504 (17. 2) IU/mL. Tinzaparin absorption: Subcutaneous injection - about 90% when measured as anti-Xa activity versus 67% for anti-IIa activity. The volume of distribution of Coagulation factor X human is Following a single intravenous dose of 25 IU/kg, the mean volume of distribution at steady state (CV%) was 56. 3 (24. 0) mL/kg. The volume of distribution of Tinzaparin is Anti-Xa activity is 4 L. Anti-IIa activity is 10. 9 L. No protein binding information is available for Coagulation factor X human. Tinzaparin is Low protein binding compared to unfractionated heparin. bound to plasma proteins. No metabolism information is available for Coagulation factor X human. Tinzaparin metabolism: Sulfation and polymerization occurs in the liver. Coagulation factor X human is eliminated via No route of elimination available. Tinzaparin is eliminated via Linear elimination through kidneys. The half-life of Coagulation factor X human is Following a single intravenous dose of 25 IU/kg, the mean plasma half-life (CV%) was 30. 3 (22. 8) hr. The half-life of Tinzaparin is Anti-Xa activity is 82 minutes. Anti-IIa activity is 71 minutes. The clearance of Coagulation factor X human is Following a single intravenous dose of 25 IU/kg, the mean total body clearance was 1. 35 (21. 7) mL/kg/hr. The clearance of Tinzaparin is Clearance is dose-dependant. The clearance of tinzaparin based on anti-Xa activity ranged from 1. 14 to 2. 04 L/hr. No toxicity information is available for Coagulation factor X human. Tinzaparin toxicity includes Osteoporosis with increasing duration of use, bleeding, alopecia, heparin induced thrombocytopenia (HIT). All of these adverse drug reactions occur less with LMWH compared to unfractionated heparin. Tinzaparin showed no toxic effects at doses up to 5 mg/kg in mice, rats, or dogs in standard acute, subacute, and chronic toxicity studies. Brand names of Coagulation factor X human include Balfaxar, Beriplex, Coagadex, Kcentra, Octaplex. Brand names of Tinzaparin include Innohep. No synonyms are available for Coagulation factor X human. No synonyms are available for Tinzaparin. Coagulation factor X human summary: It is Coagulation factor X human is a coagulation factor used to treat Factor X deficiency to control bleeding. Tinzaparin summary: It is Tinzaparin is a low molecular weight heparin used for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin. Answer: Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents.

Coagulation factor X human

Drug A is Abatacept. Drug B is Fluocinonide. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Fluocinonide is combined with Abatacept. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Abatacept is indicated for Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. Fluocinonide is indicated for A topical anti-inflammatory product for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Abatacept pharmacodynamics: Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. Fluocinonide pharmacodynamics: Fluocinonide is a potent glucocorticoid steroid used topically as anti-inflammatory agent for the treatment of skin disorders such as eczema. It mediates its effects to relieve itching, redness, dryness, crusting, scaling, inflammation, and discomfort associated with inflammatory skin conditions. The mechanism of action of Abatacept is that it Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. The mechanism of action of Fluocinonide is that it Fluocinonide is a potent glucocorticoid steroid used topically as anti-inflammatory agent for the treatment of skin disorders such as eczema. Fluocinonide binds to the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. Cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In another words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids. Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc. ) from neutrophils, macrophages and mastocytes. Additionally the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. Like other glucocorticoid agents Fluocinolone acetonide acts as a physiological antagonist to insulin by decreasing glycogenesis (formation of glycogen). It also promotes the breakdown of lipids (lipolysis), and proteins, leading to the mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood). There is also decreased glycogen formation in the liver. Abatacept absorption: When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78. 6%. Fluocinonide absorption: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. In general, percutaneous absorption is minimal. The volume of distribution of Abatacept is 0. 07 L/kg [RA Patients, IV administration]. 0. 09 L/kg [Healthy Subjects, IV administration] 0. 11 L/kg [RA patients, subcutaneous administration] No volume of distribution information is available for Fluocinonide. No protein binding information is available for Abatacept. No protein binding information is available for Fluocinonide. No metabolism information is available for Abatacept. No metabolism information is available for Fluocinonide. Abatacept is eliminated via Kidney and liver. Fluocinonide is eliminated via Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. The half-life of Abatacept is 16. 7 (12-23) days in healthy subjects;. 13. 1 (8-25) days in RA subjects; 14. 3 days when subcutaneously administered to adult RA patients. The half-life of Fluocinonide is No half-life available. The clearance of Abatacept is 0. 23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion]. 0. 22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0. 4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0. 28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. No clearance information is available for Fluocinonide. Abatacept toxicity includes Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. Fluocinonide toxicity includes Side effects may include acne-like eruptions, burning, dryness, excessive hair growth, infection of the skin, irritation, itching, lack of skin colour, prickly heat, skin inflammation, skin loss or softening, stretch marks. Brand names of Abatacept include Orencia. Brand names of Fluocinonide include Lidemol, Lidex, Lyderm, Tiamol, Vanos. No synonyms are available for Abatacept. No synonyms are available for Fluocinonide. Abatacept summary: It is Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. Fluocinonide summary: It is Fluocinonide is a high potency corticosteroid commonly used topically for a number of inflammatory skin conditions. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Abatacept

Drug A is Abemaciclib. Drug B is Hydrocortisone. The severity of the interaction is major. The metabolism of Abemaciclib can be increased when combined with Hydrocortisone. The subject drug is a CYP3A4 enzyme inducer of unknown strength, and the affected drug is metabolized by the CYP3A4 enzyme. Concomitant administration of these agents will induce the metabolism of the CYP3A4 substrate (affected drug), reducing the serum concentration and therapeutic effect. Drugs with a narrow therapeutic index must be maintained within a specific concentration range in order to be safe and efficacious. Reduced concentration of a drug with a narrow therapeutic index may lead to significantly lower efficacy. Abemaciclib is indicated for Indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. Inidicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Hydrocortisone is indicated for Otic solutions are indicated for infections of the external auditory canal caused by susceptible organisms and with inflammation. Hydrocortisone tablets are indicated for certain endocrine, rheumatic, collagen, allergic, ophthalmic, respiratory, hematologic, neoplastic, edematous, gastrointestinal, and other conditions. A hydrocortisone enema is indicated for ulcerative colitis, a topical ointment with antibiotics is indicated for corticosteroid responsive dermatoses with infections, and a topical cream with acyclovir is indicated to treat cold sores. Oral granules of hydrocortisone are used as a replacement therapy for Adrenocortical Insufficiency (AI) in children under 17 years of age. Abemaciclib pharmacodynamics: In combination with fulvestrant, the progression-free survival for patients with HR-positive, HER2-negative breast cancer was 16. 4 months compared to 9. 3 months for patients taking a placebo with fulvestrant. As a monotherapy, 19. 7% of patients taking abemaciclib achieved complete or partial shrinkage of their tumors for a median 8. 6 months after treatment. Abemaciclib induces cell cycle arrest and exerts an antitumor activity in human tumor xenograft models. In patient investigations and a healthy volunteer study, abemaciclib is not shown to induce any clinically significant changes in the QTc interval. Hydrocortisone pharmacodynamics: Hydrocortisone binds to the glucocorticoid receptor leading to downstream effects such as inhibition of phospholipase A2, NF-kappa B, other inflammatory transcription factors, and the promotion of anti-inflammatory genes. Hydrocortisone has a wide therapeutic index and a moderate duration of action. Patients should stop taking the medication if irritation or sensitization occurs. The mechanism of action of Abemaciclib is that it Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and tumor formation in various cancers. G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway. Activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins, which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb. Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point. This leads to increased expression of downstream signalling molecules and activity of protein kinases that promote the cell cycle progression and initiation of DNA replication. Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing. Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. Unlike other CDK inhibitors such as Palbociclib and Ribociclib, abemaciclib exhibits greater selectivity for CDK4 compared to CDK6. The mechanism of action of Hydrocortisone is that it The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. Abemaciclib absorption: The plasma concentration of the drug increases in a dose-proportional manner. Following a single oral dose administration of 200 mg abemaciclib, the mean peak plasma concentration (Cmax) of 158 ng/mL is reached after 6 hours. The median time to reach maximum plasma concentration (Tmax) ranges from 4-6 hours following an oral administration of abemaciclib over a range of 50–275 mg, but may range up to 24 hours. The absolute bioavailability of the drug is reported to be 45%. Hydrocortisone absorption: Oral hydrocortisone at a dose of 0. 2-0. 3mg/kg/day reached a mean Cmax of 32. 69nmol/L with a mean AUC of 90. 63h*nmol/L A 0. 4-0. 6mg/kg/day dose reached a mean Cmax of 70. 81nmol/L with a mean AUC of 199. 11h*nmol/L. However, the pharmacokinetics of hydrocortisone can vary by 10 times from patient to patient. Topical hydrocortisone cream is 4-19% bioavailable with a Tmax of 24h. Hydrocortisone retention enemas are have a bioavailability of 0. 810 for slow absorbers and 0. 502 in rapid absorbers. Slow absorbers take up hydrocortisone at a rate of 0. 361±0. 255/h while fast absorbers take up hydrocortisone at a rate of 1. 05±0. 255/h. A 20mg IV dose of hydrocortisone has an AUC of 1163±277ng*h/mL. The volume of distribution of Abemaciclib is The geometric mean systemic volume of distribution is approximately 690. 3 L (49% CV). The volume of distribution of Hydrocortisone is Total hydrocortisone has a volume of distribution of 39. 82L, while the free fraction has a volume of distribution of 474. 38L. Abemaciclib is According to in vitro models using animal brain tissues, the protein binding of abemaciclib is approximately 95-98%. While abemaciclib demonstrated in vitro binding to serum albumin, alpha-1-acid glycoprotein and other human plasma proteins in a concentration-depedent manner, its major metabolites are also shown to bind to plasms proteins as well. The approximate bound fractions of M2, M18 and M20 are 93. 4%, 96. 8% and 97. 8%, respectively. bound to plasma proteins. Hydrocortisone is Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. Hydrocortisone is 90. 1% bound to proteins in plasma, with 56. 2% bound to albumin. bound to plasma proteins. Abemaciclib metabolism: Abemaciclib mainly undergoes hepatic metabolism mediated by CYP3A4. The major metabolite formed is N-desethylabemaciclib (M2), while other metabolites hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1) are also formed. M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively. Hydrocortisone metabolism: Hydrocortisone is metabolised to 6-beta hydrocortisol via CYP3A, 5-beta tetrahydrocortisol via 3-oxo-5-beta-steroid 4-dehydrogenase, 5-alpha tetrahydrocortisol via 3-oxo-5-alpha-steroid 4-dehydrogenase 2, cortisone via Corticosteroid 11-beta-dehydrogenase isozyme 1 and Corticosteroid 11-beta-dehydrogenase isozyme 2, and glucuronide products. Cortisone is further metabolized to tetrahydrocortisone and dihydrocortisol. Abemaciclib is eliminated via Following a single oral dose of 150mg radiolabeled abemaciclib, approximately 81% of the total dose was recovered in feces while 3% of the dose was detected in urine. The majority of the drug is exceted as metabolites. Hydrocortisone is eliminated via Corticosteroids are eliminated predominantly in the urine. However, data regarding the exact proportion is not readily available. The half-life of Abemaciclib is The mean plasma elimination half-life for abemaciclib in patients was 18. 3 hours (72% CV). The half-life of Hydrocortisone is Total hydrocortisone via the oral route has a half life of 2. 15h while the free fraction has a half life of 1. 39h. A 20mg IV dose of hydrocortisone has a terminal half life of 1. 9±0. 4h. The clearance of Abemaciclib is The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26. 0 L/h (51% CV). The clearance of Hydrocortisone is Total hydrocortisone by the oral route has a mean clearance of 12. 85L/h, while the free fraction has a mean clearance of 235. 78L/h. A 20mg IV dose of hydrocortisone has a clearance of 18. 2±4. 2L/h. Abemaciclib toxicity includes According to the bacterial reverse mutation (Ames) assay, abemaciclib and its active metbolites M2 and M20 did not display mutagenic properties. Abemaciclib was not clastogenic in vitro rat bone marrow micronucleus assay. Repeat-dose toxicity studies were performed to assess the effects of abemaciclib in testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0. 3 mg/kg/day in dogs which exceed the recommeded therapeutic doses in humans. The findings included decreased organ weights, intratubular cellular debris, hypospermia, tubular distillation, atrophy and degeneration or necrosis. Hydrocortisone toxicity includes Data regarding acute overdoses of glucocorticoids are rare. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment. Brand names of Abemaciclib include Verzenio. Brand names of Hydrocortisone include Ala-cort, Ala-scalp, Alcortin, Alkindi, Anusol HC, Aquanil HC, Casporyn HC, Cipro, Cipro HC, Colocort, Cortaid, Cortane-B, Cortef, Cortenema, Cortisporin, Cortizone-10, Dermacort, Dermarest Eczema, Dermazene, Home Papkit, Hydroskin, Monistat Itch Relief, Preparation H Hydrocortisone, Procto-med, Procto-pak, Proctocort, Proctol, Proctosedyl, Proctosol, Proctozone HC, Scalpicin Itch Relief, Texacort, Vanoxide-HC, Xerese. No synonyms are available for Abemaciclib. No synonyms are available for Hydrocortisone. 17-Hydroxycorticosterone Cortisol Hidrocortisona Hydrocortisone Hydrocortisonum Kendall's compound F Reichstein's substance M Abemaciclib summary: It is Abemaciclib is a medication used to treat HR+ HER2- advanced or metastatic breast cancer. Hydrocortisone summary: It is Hydrocortisone is a glucocorticoid used to treat corticosteroid-responsive dermatoses, endocrine disorders, immune conditions, and allergic disorders. Answer: The subject drug is a CYP3A4 enzyme inducer of unknown strength, and the affected drug is metabolized by the CYP3A4 enzyme. Concomitant administration of these agents will induce the metabolism of the CYP3A4 substrate (affected drug), reducing the serum concentration and therapeutic effect. Drugs with a narrow therapeutic index must be maintained within a specific concentration range in order to be safe and efficacious. Reduced concentration of a drug with a narrow therapeutic index may lead to significantly lower efficacy.

Abemaciclib

Drug A is Bumetanide. Drug B is Piroxicam. The severity of the interaction is moderate. The therapeutic efficacy of Bumetanide can be decreased when used in combination with Piroxicam. NSAIDs have been shown to decrease the natriuretic response to loop diuretics. The effect is presumably because the increased renal flow is restricted by NSAIDs. Bumetanide is indicated for the treatment of edema associated with congestive heart failure, hepatic and renal disease including the nephrotic syndrome. Piroxicam is indicated for treatment of osteoarthritis and rheumatoid arthritis. Bumetanide pharmacodynamics: Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in patients in whom high doses of furosemide are ineffective. There is however no reason not to use bumetanide as a first choice drug. The main difference between the two substances is in bioavailability. Bumetanide has more predictable pharmacokinetic properties as well as clinical effect. In patients with normal renal function, bumetanide is 40 times more effective than furosemide. Piroxicam pharmacodynamics: Piroxicam is in a class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). Piroxicam works by reducing hormones that cause inflammation and pain in the body. Piroxicam is used to reduce the pain, inflammation, and stiffness caused by rheumatoid arthritis and osteoarthritis. The mechanism of action of Bumetanide is that it Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. The mechanism of action of Piroxicam is that it The antiinflammatory effect of Piroxicam may result from the reversible inhibition of cyclooxygenase, causing the peripheral inhibition of prostaglandin synthesis. The prostaglandins are produced by an enzyme called Cox-1. Piroxicam blocks the Cox-1 enzyme, resulting into the disruption of production of prostaglandins. Piroxicam also inhibits the migration of leukocytes into sites of inflammation and prevents the formation of thromboxane A2, an aggregating agent, by the platelets. Bumetanide absorption: Bumetanide is completely absorbed (80%), and the absorption is not altered when taken with food. Bioavailability is almost complete. Piroxicam absorption: Well absorbed following oral administration. No volume of distribution information is available for Bumetanide. The volume of distribution of Piroxicam is 0. 14 L/kg. Bumetanide is 97% bound to plasma proteins. No protein binding information is available for Piroxicam. Bumetanide metabolism: 45% is secreted unchanged. Urinary and biliary metabolites are formed by oxidation of the N-butyl side chain. Piroxicam metabolism: Renal. Bumetanide is eliminated via Oral administration of carbon-14 labeled Bumex to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Biliary excretion of Bumex amounted to only 2% of the administered dose. Piroxicam is eliminated via Piroxicam and its biotransformation products are excreted in urine and feces, with about twice as much appearing in the urine as in the feces. Approximately 5% of a piroxicam dose is excreted unchanged. However, a substantial portion of piroxicam elimination occurs by hepatic metabolism. Piroxicam is excreted into human milk. The half-life of Bumetanide is 60-90 minutes. The half-life of Piroxicam is 30 to 86 hours. The clearance of Bumetanide is 0. 2 - 1. 1 mL/min/kg [preterm and full-term neonates with respiratory disorders]. 2. 17 mL/min/kg [neonates receiving bumetanide for volume overload] 1. 8 +/- 0. 3 mL/min/kg [geriatric subjects] 2. 9 +/- 0. 2 mL/min/kg [younger subjects] No clearance information is available for Piroxicam. Bumetanide toxicity includes Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels. Piroxicam toxicity includes Symptoms of overdose include drowsiness, nausea, stomach pain, and/or vomiting. Brand names of Bumetanide include Bumex, Burinex. Brand names of Piroxicam include Feldene. No synonyms are available for Bumetanide. Bumetanide Bumetanidum No synonyms are available for Piroxicam. Piroxicam betadex Piroxicamum Pyroxycam Bumetanide summary: It is Bumetanide is a sulfamyl diuretic used to treat edema in congestive heart failure, hepatic and renal disease, and nephrotic syndrome. Piroxicam summary: It is Piroxicam is an NSAID used to treat the symptoms of osteoarthritis and rheumatoid arthritis. Answer: NSAIDs have been shown to decrease the natriuretic response to loop diuretics. The effect is presumably because the increased renal flow is restricted by NSAIDs.

Bumetanide

Drug A is Adagrasib. Drug B is Dactinomycin. The severity of the interaction is major. The serum concentration of Dactinomycin can be increased when it is combined with Adagrasib. The concurrent administration of P-glycoprotein (P-gp) inhibitors and P-gp substrates with a narrow therapeutic index may inhibit their efflux out of cells, increasing drug exposure and adverse effects. This may lead to life-threatening consequences and produce unexpectedly severe adverse effects in the patients relative to the dose administered. Increased exposure to anticancer drugs, many of which are substrates of P-gp, may result in severe infection and organ toxicity. Adagrasib is indicated for Adagrasib is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s). Dactinomycin is indicated for the treatment of Wilms' tumor, childhood rhabdomyosarcoma, Ewing's sarcoma and metastatic, nonseminomatous testicular cancer as part of a combination chemotherapy and/or multi-modality treatment regimen. Adagrasib pharmacodynamics: The exposure-response relationship and pharmacodynamic response time course of adagrasib have not been elucidated. The use of adagrasib can cause QTc interval prolongation. The increase in QTc is concentration-dependent. In patients given 600 mg of adagrasib twice daily, the mean QTcF change from baseline (ΔQTcF) was 18 ms at the mean steady-state maximum concentration. The use of adagrasib can also lead to severe gastrointestinal adverse reactions, hepatotoxicity and interstitial lung disease/pneumonitis. Dactinomycin pharmacodynamics: Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases. Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implant. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis. The mechanism of action of Adagrasib is that it In normal cells, KRAS is activated by binding to guanosine triphosphate (GTP), and this promotes the activation of the MAP kinase pathway and intracellular signal transduction. When GTP is hydrolyzed to guanosine diphosphate (GDP), KRAS is inactivated. This mechanism works as an "on"/"off" system that regulates cell growth. The substitution of Gly12 by cysteine in KRAS (KRAS ) impairs GTP hydrolysis, and maintains KRAS in its active form. Therefore, the presence of this mutation leads to uncontrolled cellular proliferation and growth, as well as malignant transformation. Adagrasib is a covalent inhibitor of KRAS that irreversibly and selectively binds and locks KRAS in its inactive, guanosine diphosphate–bound state. Therefore, the use of adagrasib inhibits tumor cell growth and viability in cancers with KRAS mutations with minimal off-target activity. The mechanism of action of Dactinomycin is that it Good evidence exists that this drug bind strongly, but reversibly, to DNA, interfering with synthesis of RNA (prevention of RNA polymerase elongation) and, consequently, with protein synthesis. Adagrasib absorption: The AUC and Cmax of adagrasib increase in a dose-proportional manner between 400 mg and 600 mg (0. 67 to 1 times the approved recommended dose). At the recommended dose, adagrasib reached steady-state within 8 days, with a 6-fold accumulation. The Tmax of adagrasib is approximately 6 hours. The administration of a high-fat and high-calorie meal (900-1000 calories, 50% from fat) did not have a clinically significant effect on the pharmacokinetics of adagrasib. Adagrasib has high oral bioavailability and is able to penetrate the central nervous system. Dactinomycin absorption: poorly absorbed from gastrointestinal tract. The volume of distribution of Adagrasib is Adagrasib has an apparent volume of distribution of 942 L. No volume of distribution information is available for Dactinomycin. Adagrasib is In vitro, adagrasib has a human plasma protein binding of 98%. bound to plasma proteins. Dactinomycin is 5% bound to plasma proteins. Adagrasib metabolism: Following single-dose administration, adagrasib is mainly metabolized by CYP3A4. However, since adagrasib inhibits CYP3A4 following multiple dosing, other enzymes such as CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6 contribute to its metabolism at steady-state. Dactinomycin metabolism: hepatic. Adagrasib is eliminated via Adagrasib is eliminated through feces and urine. In patients given a single dose of radiolabeled adagrasib, 75% of the dose was recovered in feces (14% as unchanged), while 4. 5% was recovered in urine (2% as unchanged). Dactinomycin is eliminated via No route of elimination available. The half-life of Adagrasib is Adagrasib has a terminal elimination half-life of 23 hours. The half-life of Dactinomycin is 36 hours. The clearance of Adagrasib is Adagrasib has an apparent oral clearance (CL/F) of 37 L/h. No clearance information is available for Dactinomycin. Adagrasib toxicity includes Toxicity information regarding adagrasib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hepatotoxicity, gastrointestinal adverse reactions and QTc interval prolongation. Symptomatic and supportive measures are recommended. The carcinogenicity of adagrasib has not been evaluated. In an in vitro bacterial reverse mutation (Ames) assay, adagrasib was not mutagenic. An in vitro chromosomal aberration assay and an in vivo micronucleus assay in rats showed that it was not genotoxic. Studies evaluating the effects of adagrasib on fertility have not been performed. The oral administration of adagrasib to rats for up to 13 weeks induced phospholipidosis at doses higher than 150 mg/kg (approximately 2 times the human exposure at the recommended dose based on AUC). The presence of phospholipidosis led to the increased vacuolation of multiple organs. Dactinomycin toxicity includes hepatoxicity. Brand names of Adagrasib include Krazati. Brand names of Dactinomycin include Cosmegen. No synonyms are available for Adagrasib. No synonyms are available for Dactinomycin. ActD Actinomycin C1 Actinomycin D ACTINOMYCIN I1 Actinomycin IV ACTINOMYCIN X1 ACTINOMYCIN-D ANA-conjugated dactinomycin nanoemulsion Dactinomicina Dactinomycin Dactinomycine Dactinomycinum DILACTONE ACTINOMYCIN D ACID Meractinomycin N,N'-((2-AMINO-4,6-DIMETHYL-3-OXO-3H-PHENOXAZINE-1,9-DIYL)-BIS(CARBONYLIMINO(2-HYDROXYPROPYLIDENE)CARBONYLIMINOISOBUTYLIDENECARBONYL-1,2-PYRROLIDINEDIYLCARBONYL(METHYLIMINO)METHYLENECARBONYL))BIS(N-METHYL-L-VALINE) DILACTONE ONCOSTATIN K Adagrasib summary: It is Adagrasib is a KRAS inhibitor indicated for the treatment of locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer in patients who have received at least one prior systemic therapy. Dactinomycin summary: It is Dactinomycin is an actinomycin used to treat a wide variety of cancers. Answer: The concurrent administration of P-glycoprotein (P-gp) inhibitors and P-gp substrates with a narrow therapeutic index may inhibit their efflux out of cells, increasing drug exposure and adverse effects. This may lead to life-threatening consequences and produce unexpectedly severe adverse effects in the patients relative to the dose administered. Increased exposure to anticancer drugs, many of which are substrates of P-gp, may result in severe infection and organ toxicity.

Adagrasib

Drug A is Antithrombin III human. Drug B is Chromic chloride. The severity of the interaction is minor. Chromic chloride may decrease the excretion rate of Antithrombin III human which could result in a higher serum level. The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes, they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. Antithrombin III human is indicated for Antithrombin III human is a human antithrombin (AT) indicated in patients with hereditary antithrombin deficiency for the treatment and prevention of thromboembolism and prevention of peri-operative and peri-partum thromboembolism. Chromic chloride is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN). Antithrombin III human pharmacodynamics: Hereditary AT deficiency causes an increased risk of venous thromboembolism (VTE). During high-risk situations such as surgery or trauma or for pregnant women, during the peri-partum period, the risk of development of VTEs as compared to the normal population in these situations is increased by a factor 10 to 50. In hereditary antithrombin deficient patients ATryn restores (normalize) plasma AT activity levels during peri-operative and peri-partum periods. Chromic chloride pharmacodynamics: Trivalent chromium is part of glucose tolerance factor, an essential activator of insulin-mediated reactions. Chromium helps to maintain normal glucose metabolism and peripheral nerve function. Providing chromium during TPN helps prevent deficiency symptoms including impaired glucose tolerance, ataxia, peripheral neuropathy and a confusional state similar to mild/moderate hepatic encephalopathy. The mechanism of action of Antithrombin III human is that it Antithrombin, an alpha2-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12. 5 mg/dL and is the major plasma inhibitor of thrombin. Inactivation of thrombin by AT occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an arginine reactive site on AT. AT is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin. The neutralization rate of serine proteases by AT proceeds slowly in the absence of heparin, but is greatly accelerated in the presence of heparin. As the therapeutic antithrombotic effect of heparin is mediated by AT, heparin in vivo is ineffective in the absence or near absence of AT. After administration, Antithrombin III human temporarily replaces the missing AT in patients with hereditary antithrombin deficiency. The mechanism of action of Chromic chloride is that it Metallic chromium has no biological activity. Chromium is referred as a glucose tolerance factor. This glucose tolerance factor is a complex of molecules. Glycine, cysteine, glutamic acid and nicotinic acid along with chromium form this complex. Antithrombin III human absorption: Therapeutic target plasma concentrations in patients with congenital antithrombin III deficiency range from 80–120% of values in healthy adults. At plasma concentrations ≤70% of normal, increased thrombin generation. Supraphysiologic plasma concentrations (e. g., 150–200% of normal) have increased bleeding risk in patients with sepsis and disseminated intravascular coagulation, not known whether supraphysiologic concentrations increase bleeding risk in patients with congenital antithrombin III deficiency. Chromic chloride absorption: Chromium absorption can increase with exercise. The volume of distribution of Antithrombin III human is Distributed into plasma (39%), extravascular space (49%), and vascular endothelial cells (11%). The volume of distribution of Chromic chloride is Chromium is stored in liver, spleen, soft tissue and bone. No protein binding information is available for Antithrombin III human. Chromic chloride is Chromic chloride-induced binding of protein to red cells. bound to plasma proteins. Antithrombin III human metabolism: <5% metabolized to low molecular weight breakdown products. Chromic chloride metabolism: The metabolism of chromic chloride hexahydrate in guinea pigs for 60 days after intratracheal injection of 200 ug Cr 10 min after injection, 69% of the dose remained in the lungs, & only 4% was found in the blood & liver, kidneys, spleen. By 24 hr, 45% was still in the lungs, 6% was excreted in the urine, & only a very small % was found in the other tissues. The spleen was the only tissue that showed accumulation & that occurred during the 1st 48 hr. Antithrombin III human is eliminated via Complexes of antithrombin III with thrombin or other proteinases cleared principally by liver and excreted in urine. Chromic chloride is eliminated via Most absorbed chromium is excreted rapidly in the urine, whereas unabsorbed chromium is excreted through feces. The half-life of Antithrombin III human is 2. 5 - 3. 8 hs. The half-life of Chromic chloride is 31- 41 hours. No clearance information is available for Antithrombin III human. No clearance information is available for Chromic chloride. No toxicity information is available for Antithrombin III human. Chromic chloride toxicity includes Reported toxic reactions to chromium include nausea, vomiting, ulcers of the gastrointestinal tract, renal and hepatic damage, convulsions and coma. The acute LD50 for intravenous trivalent chromium in rats was reported as 10 to 18 mg/kg. Brand names of Antithrombin III human include Thrombate III. Brand names of Chromic chloride include Multitrace-4, Multitrace-5. No synonyms are available for Antithrombin III human. No synonyms are available for Chromic chloride. Chromium trichloride chromium(3+) trichloride Chromium(III) chloride Puratronic chromium chloride Trichlorochromium Antithrombin III human summary: It is Antithrombin III human is an alpha-2-glycoprotein used to prevent thromboembolisms in patients with hereditary antithrombin III deficiency. Chromic chloride summary: It is Chromic chloride is a supplement to intravenous solutions given for total parenteral nutrition (TPN). Answer: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

Antithrombin III human

Drug A is Anakinra. Drug B is Rupatadine. The severity of the interaction is moderate. The metabolism of Rupatadine can be increased when combined with Anakinra. The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. Anakinra is indicated for Anakinra is an interleukin-1 receptor antagonist indicated for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis (RA), in patients 18 years of age or older who have failed one or more disease-modifying antirheumatic drugs (DMARDs). Anakinra can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents. Anakinra is also indicated for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID) and the treatment of Deficiency of Interleukin-1 Receptor Antagonist (DIRA). Anakinra is also used off-label for the treatment of several inflammatory diseases. The FDA has issued an emergency use authorization (EUA) for the emergency use of anakinra for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults with positive results of direct SARS-CoV-2 viral testing with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR). Since anakinra is approved for this condition under EUA, the drug should only be used when there are no alternative treatment available. Rupatadine is indicated for the symptomatic relief of nasal and non-nasal symptoms of seasonal allergic rhinitis and perennial allergic rhinitis in patients 2 years of age and older. Also used for the symptomatic relief of chronic spontaneous urticaria in patients 2 years of age and older. Anakinra pharmacodynamics: Anakinra is a recombinant human interleukin-1 receptor antagonist (IL-1Ra) that blocks the biologic activity of interleukin-1 (IL-1) by competitively inhibiting its ability to bind to the IL-1 type I receptor (IL-1RI). IL-1 production is higher in inflammatory diseases such as rheumatoid arthritis, where the amount of naturally occurring IL-1Ra cannot compete with the high level of IL-1 present. Anakinra has been associated with a higher probability of developing a severe infection, and the use of TNF blocking agents can increase this incidence. Hypersensitivity reactions have been reported in patients using anakinra. The prevalence of allergic reactions may be higher in patients with deficiency of interleukin-1 receptor antagonist (DIRA), since they lack the naturally occurring IL-1Ra. Anakinra can also decrease neutrophil counts in patients. Therefore, neutrophil counts should be assessed before initiating anakinra. Rupatadine pharmacodynamics: Rupatadine is an anti allergenic and acts to reduce allergic symptoms like urticaria, rhinorrhea, sneezing and itching. The mechanism of action of Anakinra is that it Interleukin-1 (IL-1) plays an important role in inflammation and immunological responses. Inflammatory stimuli trigger its production, and it binds to the IL-1 receptor to activate a wide variety of mechanisms. The activity of the IL-1 receptor is also regulated by a naturally occurring IL-1 receptor antagonist (IL-1Ra) that competes for the binding sites of the IL-1 receptor. In rheumatoid arthritis (RA) patients, IL-1 levels are elevated, inducing cartilage degradation and the stimulation of bone resorption, and the amount of IL-1Ra in the synovium and synovial fluid of RA patients cannot compete with the high level of IL-1 present. Anakinra is a recombinant, non-glycosylated form of IL-1Ra that competes with and inhibits IL-1 by binding to the IL-1 receptor; therefore, the administration of this drug reduces the inflammatory response in RA patients. Anakinra can also be used in the treatment of neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of interleukin-1 receptor antagonist (DIRA). Patients with NOMID have spontaneous mutations in CIAS1/NLRP3, a gene that encodes cryopyrin, an inflammasome component. When activated, the inflammasome enhances and promotes the production of IL-1β, an isoform of IL-1. DIRA is an autoinflammatory disease caused by mutations in the IL1RN gene. These mutations reduce the amount of IL-1Ra that is secreted, leading to the unopposed action of IL-1. Anakinra controls NOMID and DIRA symptoms by inhibiting IL-1 activity. The mechanism of action of Rupatadine is that it Rupatadine is a dual histamine H1 receptor and platelet activating (PAF) receptor antagonist. During allergic response mast cells undergo degranulation, releasing histamine and other substances. Histamine acts on H1 receptors to produce symptoms of nasal blockage, rhinorhea, itching, and swelling. PAF is produced from phospholipids cleaved by phospholipase A2. It acts to produce vascular leakage which contributes to rhinorhea and nasal blockage. By blocking both the H1 receptor and PAF receptor, rupatidine prevents these mediators from exerting their effects and so reduces the severity of allergic symptoms. Anakinra absorption: The bioavailability of anakinra is 95% in healthy subjects administered a 70 mg subcutaneous bolus injection. In patients with rheumatoid arthritis (RA) administered a subcutaneous dose of anakinra, the maximum plasma concentration was detected 3 to 7 hours later. No unexpected accumulation was observed in RA patients receiving this drug for up to 24 weeks. In a phase 1, single-center, randomized, sequential single-dose escalation PK study done in patients with stable RA, AUC increased in a relatively dose-proportional manner. While the t max and Cmax fluctuated across the different doses provided to these patients (range from 0. 5 to 6 mg/kg), clearance appeared to be consistent. In patients with neonatal-onset multisystem inflammatory disease (NOMID) treated with a subcutaneous dose of 3 mg/kg of anakinra for an average of 3. 5 years (n=16), Cmax was 3628 ng/mL and C 24h was 203 ng/mL. Rupatadine absorption: Rupatidine is rapidly absorbed with a Tmax of 1 h. Administration with a high fat meal increases exposure by 23% and increases Tmax to 2 h. The volume of distribution of Anakinra is In adult subjects with rheumatoid arthritis (RA) treated with anakinra (n=35), the volume of distribution averaged 18. 5 L. The volume of distribution of Rupatadine is The apparent volume of distribution is 9799 L. No protein binding information is available for Anakinra. Rupatadine is Rupatidine is 98. 5-99. 0% bound to human plasma proteins. bound to plasma proteins. Anakinra metabolism: As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body. Rupatadine metabolism: Rupatadine is metabolized by oxidation mediated primarily by CYP3A4. CYP2C9, CYP2C19, and CYP2D6 are also involved to a lesser extent. The metabolites desloratidine and hydroxylated forms of desloratidine retain some activity as H1 receptor antagonists. Anakinra is eliminated via Anakinra is mostly excreted by the kidney; therefore, the risk of toxic reactions may increase in patients with impaired renal function. Rupatadine is eliminated via No route of elimination available. The half-life of Anakinra is In patients with rheumatoid arthritis (RA), the terminal half-life of anakinra ranged from 4 to 6 hours. In patients with neonatal-onset multisystem inflammatory disease (NOMID), the median half-life of anakinra was 5. 7 h (range=3. 1-28. 2, n=12). The half-life of Rupatadine is The half life of elimination is 15. 9 h in children 2-5 years old, 12. 3 h in children 6-11 years old, 5. 9 h in adults, and 8. 7 h in geriatric patients. The clearance of Anakinra is In patients with rheumatoid arthritis (RA), the clearance of anakinra was relatively consistent for different dose levels. Clearance is variable and increases with increasing creatinine clearance and body weight. However, gender and age were not significant factors. In patients with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal impairment, the mean plasma clearance of anakinra was 16% and 50% lower, respectively. In patients with severe renal insufficiency and end-stage renal disease (creatinine clearance < 30 mL/min), the mean plasma clearance of anakinra was 70% and 75% lower, respectively. The clearance of Rupatadine is Systemic clearance is 1556. 2 L/h in young adults and 798. 2 L/h in geriatric patients. Anakinra toxicity includes In clinical trials done in patients with rheumatoid arthritis (RA) and neonatal-onset multisystem inflammatory disease (NOMID) treated with anakinra, no cases of overdose were reported. Sepsis trials were performed using mean calculated doses up to 35 times the ones given to patients with RA over 72 hours. Anakinra did not produce any serious toxicities at this dose range. In preclinical studies done in rats, where up to 100 mg/kg/day were administered either intravenously or subcutaneously over 14 days, and given at doses of 2, 20 or 200 mg/kg/day subcutaneously for 6 months, anakinra was well tolerated. Toxicity ranged from mild to moderate, and dose-related inflammation, hemorrhage and fibrosis at the injection site were detected in both rats and monkeys. The no observable adverse effect level (NOAEL) in rats receiving a daily subcutaneous dose of anakinra for 6 months was 2 mg/kg/day. In rats receiving a daily intravenous injection of anakinra for 14 or 28 days, the NOAEL was 30 mg/kg/day. The NOAEL in Rhesus monkeys was 150 mg/kg/day when anakinra was administered via intravenous infusion for 7 days, 10-30 mg/kg/day when administered via intravenous bolus injection for 14 days and 5 mg/kg/day when administered subcutaneously for 14 days. Anakinra had no effects on fertility and reproductive capacity in both male and female rats given the maximum recommended human dose. No toxicity information is available for Rupatadine. Brand names of Anakinra include Kineret. Brand names of Rupatadine include Rupall. No synonyms are available for Anakinra. No synonyms are available for Rupatadine. Anakinra summary: It is Anakinra is a recombinant form of human interleukin-1 receptor antagonist used in the treatment of rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and deficiency of interleukin-1 receptor antagonist (DIRA). Rupatadine summary: It is Rupatadine is a selective histamine H1 receptor antagonist and platelet activating factor (PAF) antagonist used to treat allergic rhinitis. Answer: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates.

Anakinra

Drug A is Aclidinium. Drug B is Ramelteon. The severity of the interaction is minor. Ramelteon may decrease the excretion rate of Aclidinium which could result in a higher serum level. The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes, they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. Aclidinium is indicated for Aclidinium bromide inhalation powder is indicated for the long-term, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Ramelteon is indicated for the treatment of insomnia characterized by difficulty with sleep onset. Aclidinium pharmacodynamics: Aclidinium does not prolong the QTc interval or have significant effects on cardiac rhythm. Ramelteon pharmacodynamics: Ramelteon is the first selective melatonin agonist. It works by mimicking melatonin (MT), a naturally occuring hormone that is produced during the sleep period and thought to be responsible for the regulation of circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has a high affinity for the MT 1 and MT 2 receptors. The MT 1 and MT 2 receptors are located in the brain's suprachiasmatic nuclei (SCN),which is known as the body's "master clock" because it regulates the 24-hour sleep-wake cycle. Ramelteon has an active metabolite that is less potent but circulates in higher concentrations than the parent compound. The metabolite also has weak affinity for the 5HT2b receptor. The mechanism of action of Aclidinium is that it Aclidinium is a long-acting, competitive, and reversible anticholinergic drug that is specific for the acetylcholine muscarinic receptors. It binds to all 5 muscarinic receptor subtypes to a similar affinity. Aclidinium's effects on the airways are mediated through the M3 receptor at the smooth muscle to cause bronchodilation. Prevention of acetylcholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The mechanism of action of Ramelteon is that it Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT 1 and MT 2 receptors, and lower selectivity for the MT 3 receptor. Melatonin production is concurrent with nocturnal sleep, meaning that an increase in melatonin levels is related to the onset of self-reported sleepiness and an increase in sleep propensity. MT 1 receptors are believed to be responsible for regulation of sleepiness and facilitation of sleep onset, and MT 2 receptors are believed to mediate phase-shifting effects of melatonin on the circadian rhythm. While MT 1 and MT 2 receptors are associated with the sleep-wake cycle, MT 3 has a completely different profile, and therefore is not likely to be involved in the sleep-wake cycle. Remelteon has no appreciable affinity for the gamma-aminobutyric acid (GABA) receptor complex or receptors that bind neuropeptides, cytokines, serotonin, dopamine, norepinephrine, acetylcholine, or opiates. Aclidinium absorption: Bioavailability, healthy subjects = 6%;. T max, healthy subjects = 10 minutes; Time to steady state, healthy subjects = 2 days; Ramelteon absorption: Rapid, total absorption is at least 84%. The volume of distribution of Aclidinium is Following IV administration, the volume of distribution is 300 L. The volume of distribution of Ramelteon is 73. 6 L. No protein binding information is available for Aclidinium. Ramelteon is ~82% (in human serum) bound to plasma proteins. Aclidinium metabolism: The major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases in the plasma. Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are pharmacologically inactive. Ramelteon metabolism: Hepatic. Aclidinium is eliminated via Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium. Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces. The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis. After dry powder inhalation, urinary excretion of aclidinium is about 0. 09% of the dose. Ramelteon is eliminated via Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0. 1% of the dose was excreted in urine and feces as the parent compound. The half-life of Aclidinium is Plasma half-life = 2. 4 minutes (indicating that aclidinium is very rapidly hydrolyzed in plasma into its two inactive metabolites and has a low chance of causing systemic side effects). Effective half-life = 5-8 hours. The half-life of Ramelteon is ~1-2. 6 hours. The clearance of Aclidinium is Total clearance, IV dose, young healthy subjects = 170 L/h (inter-individual variability of 36%). No clearance information is available for Ramelteon. Aclidinium toxicity includes Most common adverse reactions (≥3% incidence and greater than placebo) are headache, nasopharyngitis and cough. No toxicity information is available for Ramelteon. Brand names of Aclidinium include Bretaris Genuair, Duaklir, Duaklir Genuair, Eklira Genuair, Tudorza, Tudorza Genuair. Brand names of Ramelteon include Rozerem. No synonyms are available for Aclidinium. No synonyms are available for Ramelteon. Aclidinium summary: It is Aclidinium is an inhaled long-acting anticholinergic used as a maintenance bronchodilator in patients with chronic obstructive pulmonary disease (COPD). Ramelteon summary: It is Ramelteon is a melatonin receptor agonist used to treat insomnia. Answer: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

Aclidinium

Drug A is Benralizumab. Drug B is Estradiol. The severity of the interaction is minor. Estradiol may increase the thrombogenic activities of Benralizumab. Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. Benralizumab is indicated for Benralizumab is indicated as a maintenance treatment of patients 12 years or older with severe asthma and an eosinophilic phenotype. The pathology of severe asthma with eosinophilic phenotype is also denotated as TH2-high phenotype. The patients with this phenotype are characterized by the expression of IL-5 and IL-13, airway hyperresponsiveness, responsiveness to inhaled corticosteroids, high serum IgE and eosinophilia in blood and airway. In the TH2-high phenotype, IL-5 presents a central role as it is responsible for eosinophil differentiation, survival, activation and migration to the lungs. Estradiol is indicated for Estradiol is indicated in various preparations for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, and for the prevention of postmenopausal osteoporosis. It is also used for the treatment of breast cancer (only for palliation therapy) in certain men or women with metastatic disease, and for the treatment of androgen-dependent prostate cancer (only for palliation therapy). It is also used in combination with other hormones as a component of oral contraceptive pills for preventing pregnancy (most commonly as Ethinylestradiol, a synthetic form of estradiol). A note on duration of treatment Recommendations for treatment of menopausal symptoms changed drastically following the release of results and early termination of the Women's Health Initiative (WHI) studies in 2002 as concerns were raised regarding estrogen use. Specifically, the combined estrogen–progestin group was discontinued after about 5 years of follow up due to a statistically significant increase in invasive breast cancer and in cardiovascular events. Following extensive critique of the WHI results, Hormone Replacement Therapy (HRT) is now recommended to be used only for a short period (for 3-5 years postmenopause) in low doses, and in women without a history of breast cancer or increased risk of cardiovascular or thromboembolic disease. Estrogen for postmenopausal symptoms should always be given with a progestin component due to estrogen's stimulatory effects on the endometrium; in women with an intact uterus, unopposed estrogen has been shown to promote the growth of the endometrium which can lead to endometrial hyperplasia and possibly cancer over the long-term. Benralizumab pharmacodynamics: Eosinophils are the key target of inflammatory respiratory diseases and they undergo apoptosis in absence of IL-5. Therefore, benralizumab action on the IL-5 receptor in basophils and eosinophils produces the apoptosis and its significant reduction in the blood. On the other hand, Benralizumab binding to natural killer cells FcγRIIIα receptor produces a direct antibody-dependent cell-mediated cytotoxicity. All these effects produce a reduction in eosinophil count in airway mucosa, submucosa, sputum, blood and bone marrow. Estradiol pharmacodynamics: Estradiol acts on the on the estrogen receptors to relieve vasomotor systems (such as hot flashes) and urogenital symptoms (such as vaginal dryness and dyspareunia). Estradiol has also been shown to exert favorable effects on bone density by inhibiting bone resorption. Estrogen appears to inhibit bone resorption and may have beneficial effects on the plasma lipid profile. Estrogens cause an increase in hepatic synthesis of various proteins, which include sex hormone binding globulin (SHBG), and thyroid-binding globulin (TBG). Estrogens are known to suppress the formation of follicle-stimulating hormone (FSH) in the anterior pituitary gland. A note on hyper-coagulable state, cardiovascular health, and blood pressure Estradiol may cause an increased risk of cardiovascular disease, DVT, and stroke, and its use should be avoided in patients at high risk of these conditions. Estrogen induces a hyper-coagulable state, which is also associated with both estrogen-containing oral contraceptive (OC) use and pregnancy. Although estrogen causes an increase in levels of plasma renin and angiotensin. Estrogen-induced increases in angiotensin, causing sodium retention, which is likely to be the mechanism causing hypertension after oral contraceptive treatment. The mechanism of action of Benralizumab is that it Interleukin-5 (IL-5) induces an eosinophil-mediated inflammatory response by binding to the IL-5 receptor (IL-5R) expressed in eosinophils, basophils and some mast cells. Benralizumab, unlike IL-5 low-affinity binding, binds with high affinity to the domain I of the α-chain of IL-5R and blocks its signaling and the proliferation of IL-5-dependent cell lines. On the other hand, Benralizumab is an afucosylated antibody in the CH2 region which gives it a high affinity for the FcγRIIIa on natural killer cells, macrophages and neutrophils. This binding triggers a magnified apoptosis response in eosinophils via antibody-dependent cell-mediated cytotoxicity. The mechanism of action of Estradiol is that it Estrogen is found in the breast, uterine, ovarian, skin, prostate, bone, fat, and brain tissues. The main source of estrogen in adult women during the reproductive period of life is the ovarian follicle, which secretes 70 to 500 mcg of estradiol each day. After menopause, however, the majority of endogenous estrogen is produced by transformation of androstenedione (which is secreted by the adrenal cortex) to estrone in the peripheral tissues. Both estrone and its sulphate conjugated form, estrone sulphate, represent the most abundant estrogens found in postmenopausal women. Estradiol, however, is considerably more potent than estrone and estriol at the estrogen receptor (ER). As a result, the higher estrone concentration in postmenopausal population, can cause various undesirable effects. These effects may include hot flashes, chills, vaginal dryness, mood swings, irregular menstruation, and chills, in addition to sleep problems. Estradiol workings by binding to subtypes of the estrogen receptor: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). It also exerts potent agonism of G Protein-coupled estrogen receptor (GPER), which is recognized an important regulator of this drug's rapid effects. Once the estrogen receptor has bound to its ligand, it enters the nucleus of the target cell, regulating gene transcription and formation of messenger RNA. This mRNA makes contact with ribosomes producing specific proteins that express the effect of estradiol upon the target cell. Agonism of estrogen receptors increases pro-estrogenic effects, leading to the relief of vasomotor and urogenital symptoms of a postmenopausal or low estradiol state. Benralizumab absorption: Subcutaneous administration of Benralizumab presented a dose-proportional pharmacokinetic profile. The administration of 20-200 mg presented an absorption half-life of 3. 6 days with a bioavailability of 58%. It is also reported for Benralizumab a Cmax of 82 mcg/ml and AUC of 775 mcg day/ml. Estradiol absorption: The absorption of several formulations of estradiol is described below: Oral tablets and injections First-pass metabolism in the gastrointestinal tract rapidly breaks down estradiol tablets before entering the systemic circulation. The bioavailability of oral estrogens is said to be 2-10% due to significant first-pass effects. The esterification of estradiol improves the administration (such as with estradiol valerate) or to sustain release from intramuscular depot injections (including estradiol cypionate ) via higher lipophilicity. After absorption, the esters are cleaved, which leads to the release of endogenous estradiol, or 17β-estradiol. Transdermal preparations The transdermal preparations slowly release estradiol through intact skin, which sustains circulating levels of estradiol during a 1 week period of time. Notably, the bioavailability of estradiol after transdermal administration is about 20 times higher than after oral administration. Transdermal estradiol avoids first pass metabolism effects that reduce bioavailability. Administration via the buttock leads to a Cmax of about 174 pg/mL compared to 147 pg/mL via the abdomen. Spray preparations After daily administration, the spray formulations of estradiol reach steady state within 7-8 days. After 3 sprays daily, Cmax is about 54 pg/mL with a Tmax of 20 hours. AUC is about 471 pg•hr/mL. Vaginal ring and cream preparations Estradiol is efficiently absorbed through the mucous membranes of the vagina. The vaginal administration of estrogens evades first-pass metabolism. Tmax after vaginal ring delivery ranges from 0. 5 to 1 hour. Cmax is about 63 pg/mL. The vaginal cream preparation has a Cmax of estradiol (a component of Premarin vaginal estrogen conjugate cream) was a Cmax of 12. 8 ± 16. 6 pg/mL, Tmax of 8. 5 ± 6. 2 hours, with an AUC of 231 ± 285 pg•hr/mL. The volume of distribution of Benralizumab is Pharmacokinetic reports of Benralizumab showed a volume of distribution in a range of 52-93ml/kg. For a 70kg individual, the central volume of distribution of Benralizumab is 3. 2 L while the peripheral volume of distribution is reported to be 2. 5 L. The volume of distribution of Estradiol is Estrogens administered exogenously distribute in a similar fashion to endogenous estrogens. They can be found throughout the body, especially in the sex hormone target organs, such as the breast, ovaries and uterus. Benralizumab is There is no reports indicating that Benralizumab binds to plasma proteins. bound to plasma proteins. Estradiol is More than 95% of estrogens are found to circulate in the blood bound to sex hormone binding globulin (SHBG) and albumin. bound to plasma proteins. Benralizumab metabolism: As any monoclonal IgG antibody, Beralizumab is degraded by proteases widely spread in the body. Estradiol metabolism: Exogenously administered estrogens are metabolized in the same fashion as endogenous estrogens. Metabolic transformation occurs primarily in the liver and intestine. Estradiol is metabolized to estrone, and both are converted to estriol, which is later excreted in the urine. Sulfate and glucuronide conjugation estrogens also take place in the liver. Biliary secretion of metabolic conjugates are released into the intestine, and estrogen hydrolysis in the gut occurs, followed by reabsorption. The CYP3A4 hepatic cytochrome enzyme is heavily involved in the metabolism of estradiol. CYP1A2 also plays a role. Benralizumab is eliminated via Benraluzimab presents a linear pharmacokinetic without target-receptor mediated clearance. The presence of a dose-proportional pharmacokinetics suggests a rapid depletion of the target and an elimination mainly mediated through the reticuloendothelial system. Estradiol is eliminated via Estradiol is excreted in the urine with both glucuronide and sulfate conjugates. The half-life of Benralizumab is The half-life of Benralizumab is estimated to be 15-18 days. The half-life of Estradiol is The terminal half-lives for various estrogen products post oral or intravenous administration has been reported to range from 1-12 hours. One pharmacokinetic study of oral estradiol valerate administration in postmenopausal women revealed a terminal elimination half-life of 16. 9 ± 6. 0 h. A pharmacokinetic study of intravenous estradiol administration in postmenopausal women showed an elimination half-life of 27. 45 ± 5. 65 minutes. The half-life of estradiol appears to vary by route of administration. The clearance of Benralizumab is a subject weighting 70kg, the typical systemic clearance is 0. 29L/day. The clearance of Estradiol is In one pharmacokinetic study, the clearance of orally administered micronized estradiol in postmenopausal women was 29. 9±15. 5 mL/min/kg. Another study revealed a clearance of intravenously administered estradiol was 1. 3 mL/min/kg. Benralizumab toxicity includes There are not reports of long-term studies regarding tumorgenesis or carcinogenesis. Fertility studies performed in aminal trials showed no adverse histopathological findings. Estradiol toxicity includes The NOAEL (no-observed-adverse-effect-level) oral toxicity of estradiol after 90 day in rats was 0. 003 mg/kg/day for blood, female reproductive, and male reproductive, endocrine, and liver toxicity. Oral TDLO of ethinyl estradiol is 21 mg/kg/21D intermittent, woman) with an oral LD50 of 960 mg/kg in the rat. There is limited information in the literature regarding estrogen overdose. Estradiol overdose likely leads to the occurrence of estrogen-associated adverse effects, including nausea, vomiting, abdominal pain, breast tenderness, venous thrombosis, and vaginal bleeding. It is generally recommend to discontinue estradiol treatment and offer supportive care in the case of an overdose. Brand names of Benralizumab include Fasenra. Brand names of Estradiol include Activella 1/0. 5 28 Day, Activelle, Amabelz 0. 5/0. 1 28 Day, Angeliq 0. 25/0. 5 28 Day, Bijuva, Climara, Climara Pro, Combipatch, Divigel, Dotti, Elestrin, Estalis, Estrace, Estradot, Estring, Estrogel, Etyqa 0. 5/0. 1 28 Day, Evamist, Imvexxy 4 Mcg Starter Pack, Lopreeza 1/0. 5 28 Day, Lyllana, Menostar, Mimvey, Minivelle, Myfembree, Oesclim, Oriahnn 28 Day Kit, Prefest 30 Day, Vagifem, Vivelle, Yuvafem. No synonyms are available for Benralizumab. No synonyms are available for Estradiol. beta-Estradiol cis-Estradiol Estradiol-17beta Estradiolum Benralizumab summary: It is Benralizumab is a monoclonal antibody used to treat eosinophilic asthma. Estradiol summary: It is Estradiol is an estrogenic steroid used to treat vasomotor symptoms of vulvar and vaginal atrophy in menopause, hypoestrogenism, prevention of postmenopausal osteoporosis, treatment of breast cancer, and advanced androgen-dependent carcinoma of the prostate. Answer: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders.

Benralizumab

Drug A is Acenocoumarol. Drug B is Apixaban. The severity of the interaction is major. Apixaban may increase the anticoagulant activities of Acenocoumarol. Due to a synergistic effect, concomitant use of apixaban and other anticoagulants may lead to more profound anticoagulant activities of those drugs. As with most anticoagulant drugs, apixaban increases the risk for bleeding and may cause serious, potentially fatal bleeding events. Co-administration of apixaban with other anticoagulants may significantly increase the bleeding potential of anticoagulant agents. Acenocoumarol is indicated for the treatment and prevention of thromboembolic diseases. More specifically, it is indicated for the prevention of cerebral embolism, deep vein thrombosis, pulmonary embolism, thromboembolism in infarction and transient ischemic attacks. It is used for the treatment of deep vein thrombosis and myocardial infarction. Apixaban is indicated for Apixaban is indicated for reducing the risk of stroke and systemic embolism in patients who have nonvalvular atrial fibrillation, prophylaxis of deep vein thrombosis(DVT) leading to pulmonary embolism(PE) in patients after a hip or knee replacement surgery, and treatment of DVT and PE to reduce the risk of recurrence. Acenocoumarol pharmacodynamics: Acenocoumarol inhibits the reduction of vitamin K by vitamin K reductase. This prevents carboxylation of certain glutamic acid residues near the N-terminals of clotting factors II, VII, IX and X, the vitamin K-dependent clotting factors. Glutamic acid carboxylation is important for the interaction between these clotting factors and calcium. Without this interaction, clotting cannot occur. Both the extrinsic (via factors VII, X and II) and intrinsic (via factors IX, X and II) are affected by acenocoumarol. Apixaban pharmacodynamics: Apixaban selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III. Apixaban also inhibits prothrominase. These effects prevent the formation of a thrombus. The mechanism of action of Acenocoumarol is that it Acenocoumarol inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent clotting factors, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited resulting in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots. The mechanism of action of Apixaban is that it Apixaban selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III. Apixaban also inhibits prothrominase. These effects prevent the formation of a thrombus. Acenocoumarol absorption: Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration. Apixaban absorption: Apixaban is approximately 50% bioavailable though other studies report 43-46% oral bioavailability. The volume of distribution of Acenocoumarol is The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses < or = 20 microg/kg and 88 ml/kg for doses > 20 microg/kg respectively. The volume of distribution of Apixaban is Approximately 21L. Acenocoumarol is 98. 7% protein bound, mainly to albumin bound to plasma proteins. Apixaban is 92-94%. bound to plasma proteins. Acenocoumarol metabolism: Extensively metabolized in the liver via oxidation forming two hydroxy metabolites and keto reduction producing two alcohol metabolites. Reduction of the nitro group produces an amino metabolite which is further transformed to an acetoamido metabolite. Metabolites do not appear to be pharmacologically active. Apixaban metabolism: 50% of the orally administered dose is excreted as the unchanged parent compound, however 25% of the dose is excreted as O-demethyl apixaban sulfate. All apixaban metabolites account for approximately 32% of the excreted dose though the structure of all metabolites are not well defined. Apixaban is mainly metabolized by cytochrome p450(CYP)3A4 and to a lesser extent by CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2. Acenocoumarol is eliminated via Mostly via the kidney as metabolites. Apixaban is eliminated via 56% of an orally administered dose is recovered in the feces and 24. 5-28. 8% of the dose is recovered in the urine. 83-88% of the dose recovered in the urine was the unchanged parent compound. The half-life of Acenocoumarol is 8 to 11 hours. The half-life of Apixaban is 12. 7±8. 55h. No clearance information is available for Acenocoumarol. The clearance of Apixaban is 3. 3L/h though other studies report 4876mL/h. Acenocoumarol toxicity includes The onset and severity of the symptoms are dependent on the individual's sensitivity to oral anticoagulants, the severity of the overdosage, and the duration of treatment. Bleeding is the major sign of toxicity with oral anticoagulant drugs. The most frequent symptoms observed are: cutaneous bleeding (80%), haematuria (with renal colic) (52%), haematomas, gastrointestinal bleeding, haematemesis, uterine bleeding, epistaxis, gingival bleeding and bleeding into the joints. Further symptoms include tachycardia, hypotension, peripheral circulatory disorders due to loss of blood, nausea, vomiting, diarrhoea and abdominal pains. Apixaban toxicity includes Animal studies have shown an increased risk of maternal bleeding during pregnancy but no increase in fetal malformations or fetal or maternal deaths. It is unknown if this animal data also translates to humans so apixaban should only be used in pregnancy if the benefits outweigh the risks. It is not know whether apixaban is safe and effective in labor and during birth, though animal studies have shown an increased rate of maternal bleeding. Animal studies in rats show apixaban excreted in milk, though it is not know if this also applies to humans. Nursing mothers should either stop breastfeeding or stop taking apixaban depending on the risk and benefit of each option. Studies to determine safety and effectiveness in pediatric patients have yet to be performed. Studies that involved geriatric patients (at least 75 years old) saw no difference in safety or effectiveness compared to younger patients, though geriatric patients at an especially advanced age may be more susceptible to adverse effects. Dosage adjustments for patients with end stage renal disease(ESRD) are based on estimates of pharmacokinetic principles and not clinical study. Patients with ESRD may experience pharmacodynamics similar to those seen in well controlled studies but it may not lead to the same clinical effects. Dosage adjustments are not necessary in mild hepatic impairment. In moderate hepatic impairment patients may already experience abnormalities in coagulation and so no dose recommendations are possible. Apixaban is not recommended for patients with severe hepatic impairment. Brand names of Acenocoumarol include No brand names available. Brand names of Apixaban include Eliquis. No synonyms are available for Acenocoumarol. Acénocoumarol Acenocoumarol Acenocoumarolum Acenocumarol Acenocumarolo Acenokumarin Nicoumalone Nicumalon Nitrovarfarian Nitrowarfarin No synonyms are available for Apixaban. Acenocoumarol summary: It is Acenocoumarol is an anticoagulant drug used in the prevention of thromboembolic diseases in infarction and transient ischemic attacks, as well as management of deep vein thrombosis and myocardial infarction. Apixaban summary: It is Apixaban is an anticoagulant used for the prophylaxis of stroke and systemic embolism in nonvalvular atrial fibrillation, and deep vein thrombosis(DVT) leading to pulmonary embolism(PE), including in patients after a hip or knee replacement surgery. Answer: Due to a synergistic effect, concomitant use of apixaban and other anticoagulants may lead to more profound anticoagulant activities of those drugs. As with most anticoagulant drugs, apixaban increases the risk for bleeding and may cause serious, potentially fatal bleeding events. Co-administration of apixaban with other anticoagulants may significantly increase the bleeding potential of anticoagulant agents.

Acenocoumarol

Drug A is Aldesleukin. Drug B is Pholcodine. The severity of the interaction is minor. Aldesleukin may decrease the excretion rate of Pholcodine which could result in a higher serum level. The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes, they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. Aldesleukin is indicated for treatment of adults with metastatic renal cell carcinoma. Pholcodine is indicated for Pholcodine is indicated as a cough suppressant for the temporary relief of non-productive dry cough. It is stated to present a required label indication of "temporary relief of dry cough. " Cough is the respiratory movement that occurs after an irritation signal is transmitted to the central nervous system and further stimulates the medulla oblongata. This stimulation causes a motor output that is sent through motoneurons to the respiratory muscles. A non-productive cough is a type of cough characterized by the absence of sputum, and it has a large inspiration that will cause continuous coughing. Aldesleukin pharmacodynamics: Used to treat renal cell carcinoma, Aldesleukin induces the enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, the enhancement of lymphocyte cytotoxicity, the induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and the induction of interferon-gamma production. IL-2 is normally produced by the body, secreted by T cells, and stimulates growth and differentiation of T cell response. It can be used in immunotherapy to treat cancer. It enhances the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor. Pholcodine pharmacodynamics: The therapeutic doses of pholcodine have been shown not to cause depression of respiration, CNS excitation or other side effects associated with narcotics. It is thought that the impact of pholcodine is selective on the cough center without affecting the respiratory center. Pholcodine is not euphorigenic, and thus, psychological dependence is unlikely. Clinical trials have not shown any evidence of addiction after prolonged administration of pholcodine. It is well reported that pholcodine presents a more considerable respiratory depression effect than codeine and it causes hypotension in the same degree than codeine. Some other noted impacts of pholcodine in preclinical trials are: 1) the induction of histamine release, 2) anti-histaminic effect, 3) anti-acetylcholinic action, 4) anti-convulsant action and 5) mild tranquilizing action. The mechanism of action of Aldesleukin is that it Aldesleukin binds to the IL-2 receptor which leads to heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. These events stimulate growth and differentiation of T cells. The mechanism of action of Pholcodine is that it The mechanism of action of pholcodine is directly performed in the medulla oblongata. In this site, it exerts analgesic properties on the peripheric reflexogenic receptors. This site is commonly known as the "cough center. ". No absorption information is available for Aldesleukin. Pholcodine absorption: After oral administration of 60 mg of pholcodine, the Tmax and Cmax are reported to be 1. 3 hours and 26. 3 ng/ml. In the same administration, the AUC in plasma and saliva are reported to be 1. 67 and 6. 61 mg h/l respectively. The absorption of pholcodine is reported to represent approximately 88% of the administered dose. The volume of distribution of Aldesleukin is 0. 18 l/kg. The volume of distribution of Pholcodine is The reported volume of distribution depends on the pharmacokinetic model and it can be of 265L based on a one-compartment model to 3207L in a two-compartment model. No protein binding information is available for Aldesleukin. Pholcodine is The protein binding of pholcodine is of approximately of 21-23% and it tends to have a slight variation depending if the administration is chronic. bound to plasma proteins. No metabolism information is available for Aldesleukin. Pholcodine metabolism: The metabolism of pholcodine seems to be very slow and due to the elimination profile, it is thought that most of the administered dose undergoes metabolism. There is some evidence in preclinical trials that indicate that morphine is a minor metabolite of pholcodine and that it accounts for 1% of the administered dose. Aldesleukin is eliminated via The pharmacokinetic profile of Proleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Following the initial rapid organ distribution, the primary route of clearance of circulating proleukin is the kidney. Greater than 80% of the amount of Proleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. Pholcodine is eliminated via After oral administration of pholcodine, the serum concentration peaks and declines in a monoexponential manner. The percent of the dose excreted unchanged is of approximately 25-30%. Part of the administered dose is composed by metabolites that can be recovered in urine. From the administered dose, the fecal excretion corresponds to the 5% of the administered dose as unchanged pholcodine. The half-life of Aldesleukin is 13 min-85 min. The half-life of Pholcodine is After oral administration of 60 mg of pholcodine, the half-life in plasma, saliva and urine are 45, 55 and 45 hours respectively. No clearance information is available for Aldesleukin. The clearance of Pholcodine is After oral administration of 60 mg of pholcodine, the clearance rate was reported to be 126 ml/min. No toxicity information is available for Aldesleukin. Pholcodine toxicity includes Generally, pholcodine is significantly less toxic than codeine. Nonetheless, it is important to consider the significant depressive respiratory effect. Brand names of Aldesleukin include Proleukin. Brand names of Pholcodine include No brand names available. No synonyms are available for Aldesleukin. No synonyms are available for Pholcodine. Aldesleukin summary: It is Aldesleukin is a recombinant analog of interleukin-2 used to induce an adaptive immune response in the treatment of renal cell carcinoma. Pholcodine summary: It is Pholcodine is an opioid antitussive used to suppress unproductive coughing. Answer: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

Aldesleukin

Drug A is Antithrombin Alfa. Drug B is Polythiazide. The severity of the interaction is minor. The therapeutic efficacy of Antithrombin Alfa can be decreased when used in combination with Polythiazide. The efficacy of oral anticoagulants may be reduced by the concomitant use of thiazide diuretics. 2 The evidence for this interaction is conflicting. 1 Antithrombin Alfa is indicated for Antithrombin alfa is a recombinant antithrombin it is indicated for the prevention of peri-operative and peri-partum thromboembolic events in patients with hereditary deficiency of antithrombin. Polythiazide is indicated for Polythiazide is a thiazide diuretic used to decrease edema and decrease blood pressure. Antithrombin Alfa pharmacodynamics: Hereditary antithrombin deficiency causes an increased risk of venous thromboembolism (VTE). In high risk situations, such as surgery or trauma or for pregnant women during the peri-partum period, the risk of development of VTEs is 10-50 times greater than the general population. In hereditary antithrombin deficient patients antithrombin alfa normalizes plasma antthrombin activity levels during peri-operative and peri-partum periods. Polythiazide pharmacodynamics: As a thiazide diuretic, Polythiazide inhibits the sodium-chloride symporter which decreases solute reabsorption leading to a retention of water in the urine, as water normally follows solutes. More frequent urination is due to the increased loss of water that has not been retained from the body as a result of a concomitant relationship with sodium loss from the convoluted tubule. The short-term anti-hypertensive action is based on the fact that thiazides decrease preload, decreasing blood pressure. The mechanism of action of Antithrombin Alfa is that it Antithrombin is the main inhibitor of thrombin and Factor Xa, the serine proteases involved in blood coagulation. Antithrombin neutralizes the activity of thrombin and Factor Xa by forming a complex which is rapidly removed from the circulation. The mechanism of action of Polythiazide is that it As a diuretic, polythiazide inhibits active chloride reabsorption at the early distal tubule via the thiazide-sensitive Na-Cl cotransporter (TSC), resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like polythiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of polythiazide may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle. Antithrombin Alfa absorption: Given IV so not absorbed. No absorption information is available for Polythiazide. The volume of distribution of Antithrombin Alfa is Dose of:. 50IU/kg is 126. 2 ml/kg. 100IU/kg is 156. 1 ml/kg. Vd in hereditary deficient pregnant women in high risk situations had increased Vd of 14. 3L. No volume of distribution information is available for Polythiazide. Antithrombin Alfa is Binds and inhibits thrombin and factor Xa. bound to plasma proteins. No protein binding information is available for Polythiazide. Antithrombin Alfa metabolism: Not metabolized. No metabolism information is available for Polythiazide. Antithrombin Alfa is eliminated via Irreversible complexes formed between antithrombin III and its target protease are rapidly removed by the liver. Polythiazide is eliminated via No route of elimination available. The half-life of Antithrombin Alfa is Dose of:. 50IU/kg is 11. 6 h. 100IU/kg is 17. 7 h. The half-life of Polythiazide is No half-life available. The clearance of Antithrombin Alfa is Dose of:. 50IU/kg is 9. 6 ml/hr/kg. 100IU/kg is 7. 2 ml/hr/kg. Cl in hereditary deficient pregnant women in high risk situations had increased Cl of 1. 38L/h. No clearance information is available for Polythiazide. Antithrombin Alfa toxicity includes Highest dose tested was 360mg/kg/day in rats resulted in transient limb swelling. No toxicity information is available for Polythiazide. Brand names of Antithrombin Alfa include Atryn. Brand names of Polythiazide include Minizide, Renese, Renese-R. No synonyms are available for Antithrombin Alfa. No synonyms are available for Polythiazide. Antithrombin Alfa summary: It is Antithrombin Alfa is a recombinant antithrombin used to treat peri-operative and peripartum thromboembolic events in hereditary antithrombin deficiency. Polythiazide summary: It is Polythiazide is a thiazide diuretic used in the management of hypertension and treatment of edema. Answer: The efficacy of oral anticoagulants may be reduced by the concomitant use of thiazide diuretics. 2 The evidence for this interaction is conflicting.

Antithrombin Alfa

Drug A is Bupivacaine. Drug B is Sirolimus. The severity of the interaction is moderate. The risk or severity of methemoglobinemia can be increased when Sirolimus is combined with Bupivacaine. The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antibiotics may increase the risk of developing methemoglobinemia. Bupivacaine is indicated for As an implant, bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. Bupivacaine, in liposome suspension, is indicated in patients aged 6 years and older for single-dose infiltration to produce postsurgical local analgesia. In adults, it is also indicated to produce regional analgesia via an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Bupivicaine, in combination with meloxicam, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided. Bupivacaine, alone or in combination with epinephrine, is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations are recommended for each type of block indicated to produce local or regional anesthesia or analgesia. Finally, its use is not indicated in all blocks given clinically significant risks associated with use. Sirolimus is indicated for Sirolimus is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. In patients at low-to moderate-immunologic risk, it is recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn two to four months after transplantation. In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation. It is also used to treat lymphangioleiomyomatosis. In the US, albumin-bound sirolimus for intravenous injection is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa). In Europe, it is recommended that sirolimus for the prophylaxis of organ rejection in renal transplants is used in combination with cyclosporin microemulsion and corticosteroids for two to three months. Sirolimus may be continued as maintenance therapy with corticosteroids only if cyclosporin microemulsion can be progressively discontinued. Topical sirolimus is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients six years of age and older. Bupivacaine pharmacodynamics: Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. Sirolimus pharmacodynamics: Sirolimus is an immunosuppressant drug with antifungal and antitumour effects. In animal models, sirolimus prolonged allograft survival following various organ transplants and reversed an acute rejection of heart and kidney allografts in rats. Upon oral administration of 2 mg/day and 5 mg/day, sirolimus significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at six months following transplantation compared with either azathioprine or placebo. In some studies, the immunosuppressive effect of sirolimus lasted up to six months after discontinuation of therapy: this tolerization effect is alloantigen-specific. Sirolimus potently inhibits antigen-induced proliferation of T cells, B cells, and antibody production. In rodent models of autoimmune disease, sirolimus suppressed immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis. The mechanism of action of Bupivacaine is that it Like lidocaine, bupivacaine is an amide local anesthetic that provides local anesthesia through blockade of nerve impulse generation and conduction. These impulses, also known as action potentials, critically depend on membrane depolarization produced by the influx of sodium ions into the neuron through voltage-gated sodium channels. Bupivacaine crosses the neuronal membrane and exerts its anesthetic action through blockade of these channels at the intracellular portion of their pore-forming transmembrane segments. The block is use-dependent, where repetitive or prolonged depolarization increases sodium channel blockade. Without sodium ions passing through the channel’s pore, bupivacaine stabilizes the membrane at rest and therefore prevents neurotransmission. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. While it is well-established that the main action of bupivacaine is through sodium channel block, additional analgesic effects of bupivacaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia. The mechanism of action of Sirolimus is that it Sirolimus works by inhibiting T-lymphocyte activation and proliferation stimulated by antigens and cytokines such as interleukin (IL)-2, IL-4, and IL-15. In target cells, sirolimus binds to the cytoplasmic receptor FK506-binding protein-12 (FKBP12), an immunophilin, to form an immunosuppressive complex. FKBP12-sirolimus complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, survival, mobility, and angiogenesis. mTOR regulates the downstream signalling pathways involved in cell survival, such as the phosphatidylinositol-3 kinase (PI3K)/Akt signalling pathway. Inhibition of mTOR leads to the suppression of cytokine-driven T-cell proliferation, thus the progression from the G1 to the S phase of the cell cycle is inhibited. Sirolimus also inhibits antibody production. In vitro, sirolimus and other mTOR inhibitors inhibit the production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphangioleiomyomatosis is a disorder that primarily affects the lungs. It is characterized by lung tissue infiltration, unregulated alveolar smooth muscle proliferation, and cystic destruction of parenchyma. Although infrequent, it occurs as a symptomatic pulmonary complication in tuberous sclerosis complex (TSC), which is an inherited disorder caused by mutations in TSC genes. Loss of functional TSC gene leads to the aberrant activation of the mTOR signalling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and proliferation of alveolar smooth muscle cell proliferation. Bupivacaine absorption: Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a Cmax of 54 ± 33 ng/mL, a median Tmax of 3 h, and an AUC ∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 ng*h/mL. Sirolimus absorption: In adult renal transplant patients with low- to moderate-immunologic risk, oral administration of 2 mg sirolimus led to a Cmax of 14. 4 ± 5. 3 ng/mL for oral solution and 15. 0 ± 4. 9 ng/mL for oral tablets. The t max was 2. 1 ± 0. 8 hours for oral solution and 3. 5 ± 2. 4 hours for oral tablets. In healthy subjects, the t max is one hour. In a multi-dose study, steady-state was reached six days following repeated twice-daily administration without an initial loading dose, with the average trough concentration of sirolimus increased approximately 2- to 3-fold. It is suspected that a loading dose of three times the maintenance dose will provide near steady-state concentrations within one day in most patients. The systemic availability of sirolimus is approximately 14%. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of Rapamune Oral Solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m. No volume of distribution information is available for Bupivacaine. The volume of distribution of Sirolimus is The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 L in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (V ss/F ) of sirolimus is 12 ± 8 L/kg. Bupivacaine is Bupivacaine is ~95% protein bound. bound to plasma proteins. Sirolimus is Sirolimus is 92% bound to human plasma proteins, mainly serum albumin (97%), α1-acid glycoprotein, and lipoproteins. bound to plasma proteins. Bupivacaine metabolism: Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4. Sirolimus metabolism: Sirolimus undergoes extensive metabolism in the intestinal wall and liver. Sirolimus is primarily metabolized by O-demethylation and/or hydroxylation via CYP3A4 to form seven major metabolites, including hydroxy, demethyl, and hydroxydemethyl metabolites, which are pharmacologically inactive. Sirolimus also undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Bupivacaine is eliminated via Only 6% of bupivacaine is excreted unchanged in the urine. Sirolimus is eliminated via Following oral administration of [ C] sirolimus in healthy subjects, about 91% of the radioactivity was recovered from feces and only 2. 2% of the radioactivity was detected in urine. Some of the metabolites of sirolimus are also detectable in feces and urine. The half-life of Bupivacaine is 2. 7 hours in adults and 8. 1 hours in neonates. Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 hours, depending on dose and application site. The half-life of Sirolimus is The mean ± SD terminal elimination half-life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours. No clearance information is available for Bupivacaine. The clearance of Sirolimus is In adult renal transplant patients with low- to moderate-immunologic risk, oral administration of 2 mg sirolimus led to oral clearance of 173 ± 50 mL/h/kg for oral solution and 139 ± 63 mL/h/kg for oral tablets. Bupivacaine toxicity includes The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4. 4 mg/kg with mean arterial plasma concentration of 4. 5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. Sirolimus toxicity includes Oral LD 50 of sirolimus is 800 mg/kg in rats and 2500 mg/kg in mouse. Sirolimus is a narrow therapeutic index drug. Although there are reports of overdose with sirolimus, there is limited information on overdose in the clinical setting. Symptoms of overdose are consistent with the adverse effects of sirolimus. General supportive measures are recommended in the event of an overdose. Because sirolimus has low aqueous solubility and high erythrocyte and plasma protein binding, it is not expected to be dialyzable to any significant extent. Brand names of Bupivacaine include Exparel, Kenalog, Marbeta, Marcaine, Marcaine With Epinephrine, Marvona Suik, P-Care M, P-Care MG, P-care, Posimir, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Sensorcaine, Sensorcaine With Epinephrine, Vivacaine, Xaracoll, Zynrelef. Brand names of Sirolimus include Fyarro, Hyftor, Rapamune. No synonyms are available for Bupivacaine. Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine No synonyms are available for Sirolimus. Sirolimús Sirolimus Sirolimusum Bupivacaine summary: It is Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures. Sirolimus summary: It is Sirolimus is an mTOR inhibitor immunosuppressant used to prevent organ transplant rejections, treat lymphangioleiomyomatosis, and treat adults with perivascular epithelioid cell tumors. Answer: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antibiotics may increase the risk of developing methemoglobinemia.

Bupivacaine

Drug A is Bromocriptine. Drug B is Tolcapone. The severity of the interaction is moderate. The risk or severity of CNS depression can be increased when Tolcapone is combined with Bromocriptine. Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. Bromocriptine is indicated for the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor complications. Bromocriptine has also been used off-label to treat restless legs syndrome and neuroleptic malignant syndrome. Tolcapone is indicated for Used as an adjunct to levodopa/carbidopa therapy for the symptomatic treatment of Parkinson's Disease. This drug is generally reserved for patients with parkinsonian syndrome receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to or are not candidates for other adjunctive therapies. Bromocriptine pharmacodynamics: Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D 2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D 2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 -receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT) 1D, dopamine D 3, 5-HT 1A, 5-HT 2A, 5-HT 1B, and 5-HT 2C receptors, antagonist activity on α 2A -adrenergic, α 2C, α 2B, and dopamine D 1 receptors, partial agonist activity at receptor 5-HT 2B, and inactivates dopamine D 4 and 5-HT 7 receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e. g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT 1B and 5-HT 2B receptors. Tolcapone pharmacodynamics: Tolcapone is a potent, selective, and reversible inhibitor of catechol-O-methyltransferase (COMT). In humans, COMT is distributed throughout various organs. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. COMT is responsible for the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. The mechanism of action of Bromocriptine is that it The dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. The mechanism of action of Tolcapone is that it The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa, resulting in an increase in plasma levodopa concentrations. The inhibition of COMT also causes a reduction in circulating 3-OMD as a result of decreased peripheral metabolism of levodopa. This may lead to an increase distribution of levodopa into the CNS through the reduction of its competitive substrate, 3-OMD, for transport mechanisms. Sustained levodopa concentrations presumably result in more consistent dopaminergic stimulation, resulting in greater reduction in the manifestations of parkinsonian syndrome. Bromocriptine absorption: Approximately 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1. 5 hours. Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours. Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2. 5 mg and decreased growth hormone concentrations persist for at least 4-5 hours. Tolcapone absorption: Rapidly absorbed (absolute bioavailability is about 65%). No volume of distribution information is available for Bromocriptine. The volume of distribution of Tolcapone is 9 L. Bromocriptine is 90-96% bound to serum albumin bound to plasma proteins. Tolcapone is > 99. 9% (to serum albumin) bound to plasma proteins. Bromocriptine metabolism: Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion. Tolcapone metabolism: The main metabolic pathway of tolcapone is glucuronidation. Bromocriptine is eliminated via Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. Tolcapone is eliminated via Tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0. 5% of dose) found unchanged in urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile. The half-life of Bromocriptine is 2-8 hours. The half-life of Tolcapone is 2-3. 5 hours. No clearance information is available for Bromocriptine. The clearance of Tolcapone is 7 L/h. Bromocriptine toxicity includes Symptoms of overdosage include nausea, vomiting, and severe hypotension. The most common adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension. Tolcapone toxicity includes LD 50 = 1600 mg/kg (Orally in rats). Brand names of Bromocriptine include Cycloset, Parlodel. Brand names of Tolcapone include Tasmar. No synonyms are available for Bromocriptine. Bromocriptine Bromocriptinum Bromocryptine Bromoergocriptine Bromoergocryptine No synonyms are available for Tolcapone. Tolcapona Tolcapone Tolcaponum Bromocriptine summary: It is Bromocriptine is a dopamine D2 receptor agonist used for the treatment of galactorrhea due to hyperprolactinemia and other prolactin-related conditions, as well as in early Parkinsonian Syndrome. Tolcapone summary: It is Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor used as adjunct therapy in the symptomatic management of idiopathic Parkinson's disease. Answer: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

Bromocriptine

Drug A is Abrocitinib. Drug B is Ubrogepant. The severity of the interaction is moderate. The serum concentration of Ubrogepant can be increased when it is combined with Abrocitinib. Ubrogepant is a known substrate of the P-glycoprotein transporter. 1 Although specific interaction studies have not been conducted, the concomitant use of ubrogepant with inhibitors of BCRP, such as the subject drug, may increase exposure to ubrogepant and subsequently increase the incidence and/or severity of related adverse effects. Abrocitinib is indicated for Abrocitinib is indicated for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. In the US, it is indicated to treat refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when the use of those therapies is inadvisable. Abrocitinib is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants. Ubrogepant is indicated for Ubrogepant is indicated for the acute treatment of migraine with or without aura in adults. Abrocitinib pharmacodynamics: Abrocitinib mediates anti-inflammatory effects by blocking the signalling of pro-inflammatory cytokines implicated in atopic dermatitis. It dose-dependently reduces the serum markers of inflammation in atopic dermatitis, including high sensitivity C-reactive protein (hsCRP), interleukin-31 (IL-31), and thymus and activation regulated chemokine (TARC). These changes returned to near baseline within four weeks following drug discontinuation. At two weeks of treatment, the mean absolute lymphocyte count increased, which returned to baseline by nine months of treatment. Treatment with abrocitinib was associated with a dose-related increase in B cell counts and a dose-related decrease in NK cell counts: the clinical significance of these changes is unknown. Treatment with 200 mg abrocitinib once-daily was associated with a transient, dose-dependent decrease in platelet count with the nadir occurring at a median of 24 days. Recovery of platelet count (~40% recovery by 12 weeks) occurred without discontinuation of the treatment. Ubrogepant pharmacodynamics: Ubrogepant acutely treats migraine headache pain by blocking the activity of a key transmitter involved in migraine pathogenesis. Exposure to ubrogepant can be significantly increased in patients with severe hepatic or renal insufficiency - dose adjustments are required for these patients in order to avoid excessive exposure, and ubrogepant is not recommended in patients with end-stage renal disease. The mechanism of action of Abrocitinib is that it Janus kinases (JAKs) are a family consisting of four receptor-associated kinases - JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Upon ligand binding and subsequent dimerization of cytokine and hormone receptors, receptor-associated JAKs are activated and phosphorylated. This allows the binding of Signal Transducers and Activators of Transcription (STATs), which are transcription factors. STAT binds to the receptor, and JAK phosphorylates and activates STAT to create a STAT dimer. The STAT dimer translocates to the nucleus to upregulate the gene transcription of pro-inflammatory cytokines and growth factors implicated in atopic dermatitis. Blocking the JAK-STAT pathway is advantageous, as it is an intracellular signalling pathway where many pro-inflammatory pathways converge. Each JAK plays a role in the signalling and regulation of different cytokines and immune cells. In atopic dermatitis, JAK1 is the therapeutic target of focus as it is involved in the signalling of the γc family of cytokines involved in immune responses and disease pathophysiology, including IL-2, IL-4, IL-7, IL-9, and IL-15. Abrocitinib reversibly inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. Biochemical assays demonstrate that abrocitinib is selective for JAK1 over JAK2 (28-fold), JAK3 (>340-fold), and tyrosine kinase (TYK) 2 (43-fold), as well as the broader kinome. Similarly, in cellular settings, abrocitinib preferentially inhibited cytokine-induced STAT phosphorylation by signalling pairs involving JAK1, while sparing signalling by JAK2/JAK2, or JAK2/TYK2 pairs. The relevance of inhibition of specific JAK enzymes to the drug's therapeutic effectiveness is currently unknown. The mechanism of action of Ubrogepant is that it The currently accepted theory of migraine pathophysiology considers dysfunction of the central nervous system, in particular the trigeminal ganglion, to be the root cause behind the condition. Activation of the trigeminal ganglion triggers the stimulation of trigeminal afferents that project to the spinal cord and synapse on various pain-sensing intra- and extracranial structures, such as the dura mater. Pain signals are then further transmitted via second-order ascending neurons to the brainstem, hypothalamus, and thalamic nuclei, and from there to several cortical regions (e. g. auditory, visual, motor cortices). The trigeminal ganglion appears to amplify and perpetuate the migraine headache pain through the activation of perivascular fibers and the release of molecules involved in pain generation, such as calcitonin gene-related peptide (CGRP). The α-isoform of CGRP, expressed in primary sensory neurons, is a potent vasodilator and has been implicated in migraine pathogenesis - CGRP levels are acutely elevated during migraine attacks, return to normal following treatment with triptan medications, and intravenous infusions of CGRP have been shown to trigger migraine-like headaches in migraine patients. In addition to its vasodilatory properties, CGRP appears to be a pronociceptive factor that modulates neuronal excitability to facilitate pain responses. Ubrogepant is a potent antagonist of the calcitonin gene-related peptide receptor - it competes with CGRP for occupancy at these receptors, preventing the actions of CGRP and its ability to amplify and perpetuate migraine headache pain, ultimately terminating the headache. Abrocitinib absorption: Abrocitinib is absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. The peak plasma concentrations of abrocitinib are reached within one hour. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once-daily administration. Both Cmax and AUC of abrocitinib increased dose proportionally up to 200 mg. A high-fat meal, high-calorie meal increased AUC by 26% and Cmax by 29%, and prolongs Tmax by two hours; however, there are ultimately no clinically relevant effect on abrocitinib exposures. Ubrogepant absorption: Following oral administration, Tmax occurs between 0. 7 and 1. 5 h. When administered with a high-fat meal, Tmax is delayed by approximately 2 hours and Cmax was reduced by 22% with no significant changes to the AUC. Ubrogepant exhibits dose-proportional pharmacokinetics throughout the entirety of its recommended dosing range. The volume of distribution of Abrocitinib is After intravenous administration, the volume of distribution of abrocitinib was approximately 100 L. The volume of distribution of Ubrogepant is The apparent central volume of distribution following oral administration is approximately 350 L. Abrocitinib is Approximately 64%, 37% and 29% of circulating abrocitinib and its active metabolites M1 and M2, respectively, are bound to plasma proteins. Abrocitinib and its active metabolites M1 and M2 bind predominantly to albumin and distribute equally between red blood cells and plasma. bound to plasma proteins. Ubrogepant is Ubrogepant is 87% protein-bound in vitro, although the specific proteins to which ubrogepant binds have not been elucidated. bound to plasma proteins. Abrocitinib metabolism: Abrocitinib undergoes CYP-mediated oxidative metabolism. CYP2C19 is the predominant enzyme, accounting for about 53% of drug metabolism. CYP2C9 is responsible for 30% of drug metabolism. About 11% and 6% of the drug is metabolized by CYP3A4 and CYP2B6, respectively. In a human radiolabeled study, the parent drug was the most prevalent circulating species. Polar mono-hydroxylated metabolites of abrocitinib - M1 (3-hydroxypropyl; PF-06471658), M2 (2-hydroxypropyl; PF-07055087), and M4 (pyrrolidinone pyrimidine; PF-07054874) - were also identified in the systemic circulation. M2 has a chiral center, thus has an enantiomer M3 (PF-07055090). At steady state, M2 and M4 are major metabolites and M1 is a minor metabolite. M2 has a pharmacological activity comparable to abrocitinib while M1 is less pharmacologically active than abrocitinib. M3 and M4 are inactive metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of the parent molecule (~60%) as well as M1 (~10%) and M2 (~30%) in the systemic circulation. The sum of unbound exposures of abrocitinib, M1 and M2, each expressed in molar units and adjusted for relative potencies, is referred to as the abrocitinib active moiety. Ubrogepant metabolism: Ubrogepant is eliminated primarily via metabolism, the majority of which is mediated by CYP3A4. Two circulating glucuronide conjugates, along with unchanged parent drug, were found to be the most abundant circulating components in human plasma. The glucuronide metabolites reportedly carry 6000-fold less activity at CGRP receptors and are therefore considered to be pharmacologically inert. Abrocitinib is eliminated via Abrocitinib is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose being excreted in urine as an unchanged parent drug. The metabolites of abrocitinib are excreted predominantly in urine. Pharmacokinetics data up to and including a single oral dose of 800 mg in healthy adult volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 48 hours. Ubrogepant is eliminated via The main route of elimination is fecal/biliary, while renal excretion is comparatively minor - following administration of a single oral dose to healthy subjects, approximately 42% of the dose was recovered unchanged in the feces and 6% was recovered unchanged in the urine. The half-life of Abrocitinib is The mean elimination half-lives of abrocitinib and its two active metabolites, M1 and M2, range from three to five hours. The half-life of Ubrogepant is Ubrogepant has an elimination half-life of 5-7 hours. The clearance of Abrocitinib is There is no information available. The clearance of Ubrogepant is The apparent oral clearance of ubrogepant is approximately 87 L/h. Abrocitinib toxicity includes There is no experience regarding human overdosage with abrocitinib. In clinical trials, there were no specific toxicities observed when abrocitinib was administered in single oral doses of 800 mg and 400 mg daily for 28 days. An overdose should be responded with symptomatic and supportive treatment, as there is no specific antidote for overdose with abrocitinib. Ubrogepant toxicity includes As clinical experience with ubrogepant is limited, detailed toxicity information is not readily available. Prescribing information for ubrogepant recommends a monitoring period of at least 24 hours following overdose based on its 5 to 7 hour half-life. Brand names of Abrocitinib include No brand names available. Brand names of Ubrogepant include Ubrelvy. No synonyms are available for Abrocitinib. No synonyms are available for Ubrogepant. Abrocitinib summary: It is Abrocitinib is a kinase inhibitor used to treat moderate-to-severe atopic dermatitis in adults. Ubrogepant summary: It is Ubrogepant is an oral CGRP antagonist used in the acute treatment of migraine with or without aura. Answer: Ubrogepant is a known substrate of the P-glycoprotein transporter. 1 Although specific interaction studies have not been conducted, the concomitant use of ubrogepant with inhibitors of BCRP, such as the subject drug, may increase exposure to ubrogepant and subsequently increase the incidence and/or severity of related adverse effects.

Abrocitinib

Drug A is Bevacizumab. Drug B is Estradiol cypionate. The severity of the interaction is minor. Estradiol cypionate may increase the thrombogenic activities of Bevacizumab. Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. Bevacizumab is indicated for As a vascular endothelial growth factor (VEGF) inhibitor, bevacizumab is used in several chemotherapy regimens to treat metastatic colorectal cancer; metastatic, unresectable, locally advanced or recurrent non-squamous non-small cell lung cancer; metastatic renal cell carcinoma; metastatic, persistent, or recurrent cervical cancer; primary peritoneal cancer; epithelial ovarian cancer; fallopian tube cancer; breast cancer; and recurrent glioblastoma. Interestingly, bevacizumab is currently under investigation for the treatment of COVID-19 complications including acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Estradiol cypionate is indicated for Depo-Estradiol intramuscular depot injection is indicated for the treatment of moderate to severe vasomotor symptoms and hypoestrogenism due to hypogonadism. Bevacizumab pharmacodynamics: Bevacizumab binds circulating vascular endothelial-derived growth factor (VEGF) and blocks it from binding to its associated receptors, effectively blunting downstream signaling. The effects of bevacizumab have been shown to re-establish normal vasculature at the tumor site resulting in increased nutrient and oxygen supply, while also improving the delivery of chemotherapeutic drugs to the target area. On the other hand, VEGF signaling is a vital component of several processes including angiogenesis, lymphangiogenesis, blood pressure regulation, wound healing, coagulation, and renal filtration. Although blocking VEGF may inhibit metastatic disease progression, it may also result in unintended effects due to the role of VEGF in several other physiologic processes. Estradiol cypionate pharmacodynamics: Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects. The mechanism of action of Bevacizumab is that it Transcription of the VEGF protein is induced by 'hypoxia inducible factor' (HIF) in a hypoxic environment. When circulating VEGF binds to VEGF receptors (VEGFR-1 and VEGFR-2) located on endothelial cells, various downstream effects are initiated. It should be noted that VEGF also binds to the neuropilin co-receptors (NRP-1 and NRP-1), leading to enhanced signaling. Cancer cells promote tumor angiogenesis by releasing VEGF, resulting in the creation of an immature and disorganized vascular network. The hypoxic microenvironment promoted by cancer cells favors the survival of more aggressive tumor cells, and gives rise to a challenging environment for immune cells to respond appropriately. As a result, VEGF has become a well-known target for anti-cancer drugs like bevacizumab. Bevacizumab is a mAb that exerts its effects by binding and inactivating serum VEGF. When bound to the mAb, VEGF is unable to interact with its cell surface receptors, and proangiogenic signalling is inhibited. This prevents formation of new blood vessels, decreases tumor vasculature, and reduces tumor blood supply. There is also evidence to suggest that VEGF is upregulated in COVID-19 patients, hence, bevacizumab is being investigated for the treatment of associated complications. Higher levels of VEGF may contribute to pulmonary edema, leading to acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Researchers are hopeful that by inhibiting VEGF, bevacizumab may effectively treat ARDS and ALI - both common features of severe COVID-19 cases. The mechanism of action of Estradiol cypionate is that it Estradiol enters target cells freely (e. g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause and of hypoestrogenism, which are primarily caused by a loss of estrogenic activity. Bevacizumab absorption: Monoclonal antibodies (mAbs) are large in size, do not readily cross cell membranes, and are unable to withstand proteolysis in the gastrointestinal tract. Given these characteristics, mAbs are poorly absorbed via the oral route and are instead administered intravenously, intramuscularly or subcutaneously. In a single dose (1mg/kg) pharmacokinetic study assessing the bioequivalence of bevacizumab and TAB008 (a biosimilar product), the pharmacokinetic parameters of Avastin (bevacizumab) were as follows:. Geometric mean Cmax = 17. 38 ug/mL Geometric mean AUCinf = 5,358 ugxh/mL Geometric mean Tmax = 2. 50 hrs Estradiol cypionate absorption: When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. The volume of distribution of Bevacizumab is The volume of distribution of bevacizumab is approximately 3. 29 L and 2. 39 L for the average male and female, respectively. The volume of distribution of Estradiol cypionate is The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Bevacizumab is >97% of serum VEGF is bound to bevacizumab. bound to plasma proteins. Estradiol cypionate is Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. bound to plasma proteins. Bevacizumab metabolism: There are several pathways through which monoclonal antibodies (mAbs) may be cleared. Non-specific clearance of mAbs refers to target independent pinocytosis, and proteolysis of the protein into small amino acids and peptides in the reticuloendothelial system (RES) and the liver. Target-mediated clearance is a result of specific interactions between the mAb and its target antigen. Once bound, the antibody-antigen complex may be cleared via lysosomal degradation. Additionally, the production of anti-drug antibodies (ADA), which are a result of an immunogenic response to mAb-based treatment, can form complexes with mAb’s and may impact the rate of mAb clearance. Estradiol cypionate metabolism: Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Bevacizumab is eliminated via Due to their size, monoclonal antibodies are not renally eliminated under normal physiological conditions. Catabolism or excretion are the primary processes of elimination. Estradiol cypionate is eliminated via Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life of Bevacizumab is The half-life of bevacizumab is estimated to be 20 days (range of 11-50 days). The half-life of Estradiol cypionate is No half-life available. The clearance of Bevacizumab is The clearance (CL) of bevacizumab is approximately 0. 207 L/day. The CL of bevacizumab can increase or decrease by 30% in patients who weigh >114 kg or <49 kg respectively. Males tend to clear bevacizumab at a faster rate than females (26% faster on average). Other factors including alkaline phosphatase (ALP), serum aspartate aminotransferase (AST), serum albumin, and tumor burden may cause the CL to fluctuate. No clearance information is available for Estradiol cypionate. Bevacizumab toxicity includes Bevacizumab toxicities are distinct from the effects of cytotoxic agents used in chemotherapy, and are normally linked to impaired VEGF function. Common toxicities associated with bevacizumab include hypertension, gastrointestinal perforation, arterial thromboembolism, reversible posterior leukoencephalopathy syndrome (RPLS), venous thromboembolism, proteinuria, bleeding/hemorrhage, and wound-healing complications. No toxicity information is available for Estradiol cypionate. Brand names of Bevacizumab include Avastin, Mvasi. Brand names of Estradiol cypionate include Depo-estradiol. No synonyms are available for Bevacizumab. No synonyms are available for Estradiol cypionate. Bevacizumab summary: It is Bevacizumab is a monoclonal anti-vascular endothelial growth factor antibody used in combination with antineoplastic agents for the treatment of many types of cancer. Estradiol cypionate summary: It is Estradiol cypionate is an estradiol prodrug used to treat vasomotor symptoms and hypoestrogenisms from hypogonadism. Answer: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders.

Bevacizumab

Drug A is Abciximab. Drug B is Cefotetan. The severity of the interaction is minor. The therapeutic efficacy of Abciximab can be decreased when used in combination with Cefotetan. Certain cephalosporins contain a N-methylthiotetrazole ring which is known to inhibit the production of vitamin K-dependent clotting factor and thus, its use can result in a prolonged prothrombin time. Coadministration of cephalosporins with anticoagulant therapies can produce a significant decrease in the therapeutic effect of the anticoagulant, producing dangerous effects. Abciximab is indicated for Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. Cefotetan is indicated for prophylaxis and treatment of bacterial infections. Abciximab pharmacodynamics: Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0. 15 mg/kg to 0. 30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0. 25 - 0. 30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. Cefotetan pharmacodynamics: Cefotetan is a semisynthetic cephamycin antibiotic that is administered intravenously or intramuscularly. The drug is highly resistant to a broad spectrum of beta-lactamases and is active against a wide range of both aerobic and anaerobic gram-positive and gram-negative microorganisms. The mechanism of action of Abciximab is that it Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. The mechanism of action of Cefotetan is that it The bactericidal action of cefotetan results from inhibition of cell wall synthesis by binding and inhibiting the bacterial penicillin binding proteins which help in the cell wall biosynthesis. No absorption information is available for Abciximab. No absorption information is available for Cefotetan. No volume of distribution information is available for Abciximab. The volume of distribution of Cefotetan is 10. 4 L [elderly patients (greater than 65 years) with normal renal function]. 10. 3 L [healthy volunteers (aged 25 to 28 years)] No protein binding information is available for Abciximab. Cefotetan is Cefotetan is 88% plasma protein bound. bound to plasma proteins. Abciximab metabolism: Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. Cefotetan metabolism: No active metabolites of cefotetan have been detected; however, small amounts (less than 7%) of cefotetan in plasma and urine may be converted to its tautomer, which has antimicrobial activity similar to the parent drug. Abciximab is eliminated via No route of elimination available. Cefotetan is eliminated via No active metabolites of cefotetan have been detected; however, small amounts (less than 7%) of cefotetan in plasma and urine may be converted to its tautomer, which has antimicrobial activity similar to the parent drug. In normal patients, from 51% to 81% of an administered dose of Cefotetan is excreted unchanged by the kidneys over a 24 hour period, which results in high and prolonged urinary concentrations. The half-life of Abciximab is Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. The half-life of Cefotetan is In volunteers with reduced renal function, the plasma half-life of cefotetan is prolonged. No clearance information is available for Abciximab. The clearance of Cefotetan is 1. 8 +/- 0. 1 L/h [elderly patients with normal renal function (. 65 years)]. 1. 8 +/- 0. 3 L/h [healthy volunteers (aged 25 to 28 years)] No toxicity information is available for Abciximab. No toxicity information is available for Cefotetan. Brand names of Abciximab include No brand names available. Brand names of Cefotetan include Cefotan. No synonyms are available for Abciximab. No synonyms are available for Cefotetan. Cefotetanum Abciximab summary: It is Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. Cefotetan summary: It is Cefotetan is an antibiotic medication used for the prophylaxis and treatment of various bacterial infections, including urinary tract infections, bone and joint infection, and lower respiratory tract infections. Answer: Certain cephalosporins contain a N-methylthiotetrazole ring which is known to inhibit the production of vitamin K-dependent clotting factor and thus, its use can result in a prolonged prothrombin time. Coadministration of cephalosporins with anticoagulant therapies can produce a significant decrease in the therapeutic effect of the anticoagulant, producing dangerous effects.

Abciximab

Drug A is Alteplase. Drug B is Estradiol cypionate. The severity of the interaction is moderate. Estradiol cypionate may decrease the anticoagulant activities of Alteplase. Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents. Alteplase is indicated for Alteplase is indicated for the treatment of acute ischemic stroke (AIS) and for use in acute myocardial infarction (AMI) for the reduction of mortality and incidence of heart failure. Alteplase is also indicated for the lysis of acute massive pulmonary embolism, defined as acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments, and acute pulmonary emboli accompanied by unstable hemodynamics. Estradiol cypionate is indicated for Depo-Estradiol intramuscular depot injection is indicated for the treatment of moderate to severe vasomotor symptoms and hypoestrogenism due to hypogonadism. Alteplase pharmacodynamics: Alteplase binds to fibrin and plasminogen. Alteplase specificity for fibrin is achieved thanks to its high affinity for lysine residues. Also, it can bind plasminogen via loop structures called kringles, stabilized by three disulphide linkages similar to the ones in plasminogen. The specificity of alteplase for plasminogen bound to fibrin allows this drug to act in a clot- or fibrin-specific manner, leading to low concentrations of circulating plasmin and a lower risk of hemorrhagic transformation. In patients with acute myocardial infarction, alteplase reduces fibrinogen levels 3 to 6 hours after treatment. In patients with acute ischemic stroke, patients treated with alteplase have a significantly higher resolution of hyperdense artery sign, a marker of clot formation in the proximal middle cerebral artery, compared to those treated with placebo. The use of alteplase increases the risk of bleeding and thromboembolic events. Rare cases of cholesterol embolism have also been reported. Estradiol cypionate pharmacodynamics: Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects. The mechanism of action of Alteplase is that it Alteplase is a recombinant tissue plasminogen activator (rt-PA) that converts plasminogen to plasmin in a fibrin-dependent process. In the absence of fibrin, alteplase converts a limited amount of plasminogen. However, in the presence of fibrin clots, alteplase binds to fibrin and cleaves the arginine-valine bond at positions 560 and 561 of plasminogen, converting it into its active form, plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus and promotes clot dissolution. Alteplase initiates local fibrinolysis with limited systemic proteolysis. The mechanism of action of Estradiol cypionate is that it Estradiol enters target cells freely (e. g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause and of hypoestrogenism, which are primarily caused by a loss of estrogenic activity. Alteplase absorption: Healthy volunteers with a baseline endogenous tissue plasminogen activator (t-PA) of 3. 3 ng/ml had a 290-fold increase in baseline concentrations after receiving alteplase at an infusion rate of 0. 25 mg/kg for 30 min; with an infusion rate of 0. 5 mg/kg, a 550-fold increase was observed. Acute myocardial infarction patients (n=12) given 10 mg of alteplase in a 2-minute infusion reached a peak plasma concentration of 3310 ng/ml. This was followed by 50 mg of alteplase in 1 h and 30 mg in 1. 5 h, resulting in steady-state plasma levels of 2210 ng/ml and 930 ng/ml, respectively. Estradiol cypionate absorption: When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. The volume of distribution of Alteplase is The initial volume of distribution approximates plasma volume. The average volume of distribution of the central compartment goes from 3. 9 to 4. 3 L, and the volume of distribution at steady state goes from 7. 2 to 12 L. The volume of distribution of Estradiol cypionate is The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Alteplase is Not available. bound to plasma proteins. Estradiol cypionate is Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. bound to plasma proteins. Alteplase metabolism: Alteplase is mainly metabolized by the liver. The carbohydrate and polypeptide domains of alteplase interact with hepatic glycoprotein receptors, leading to receptor-mediated endocytosis. In vivo studies suggest that alteplase follows zero-order kinetics, meaning that its metabolism is saturable at higher plasma concentrations. Estradiol cypionate metabolism: Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Alteplase is eliminated via In healthy volunteers, more than 80% of alteplase is eliminated through urine 18 hours after administration. Estradiol cypionate is eliminated via Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life of Alteplase is Alteplase has an initial half-life of less than 5 minutes in patients with acute myocardial infarction (AMI). The dominant initial plasma half-life of the 3-hour and the accelerated regimens for AMI are similar. The half-life of Estradiol cypionate is No half-life available. The clearance of Alteplase is Alteplase has a plasma clearance between 380 and 570 mL/min. No clearance information is available for Estradiol cypionate. Alteplase toxicity includes Toxicity information regarding alteplase is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as risk of bleeding and thromboembolic events. Symptomatic and supportive measures are recommended. The carcinogenic potential of alteplase or its effect on fertility have not been evaluated. In vivo studies evaluating tumorigenicity and in vitro studies evaluating mutagenicity were negative. It has been estimated that the acute oral and dermal toxicity of alteplase is above 5,000 mg/kg. No toxicity information is available for Estradiol cypionate. Brand names of Alteplase include Activase, Cathflo, Cathflo Activase. Brand names of Estradiol cypionate include Depo-estradiol. No synonyms are available for Alteplase. No synonyms are available for Estradiol cypionate. Alteplase summary: It is Alteplase is a recombinant form of human tissue plasminogen activator used in the emergency treatment of myocardial infarction, ischemic stroke, and pulmonary emboli. Estradiol cypionate summary: It is Estradiol cypionate is an estradiol prodrug used to treat vasomotor symptoms and hypoestrogenisms from hypogonadism. Answer: Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents.

Alteplase

Drug A is Polatuzumab vedotin. Drug B is Capsaicin. The severity of the interaction is moderate. The risk or severity of methemoglobinemia can be increased when Polatuzumab vedotin is combined with Capsaicin. The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia. Polatuzumab vedotin is indicated for Polatuzumab vedotin is used in combination with bendamustine and rituximab to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, after at least two prior therapies. In Canada, this indication is approved for patients who are not eligible for autologous stem cell transplant and have received at least one prior therapy. Polatuzumab vedotin is also used in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) to treat adult patients with previously untreated large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), high-grade B-cell lymphoma, Epstein-Barr virus-positive (EBV+) DLBCL NOS, and T-cell/histiocyte rich LBCL. Capsaicin is indicated for The capsaicin 8% patch is indicated in the treatment of neuropathic pain associated with post-herpetic neuralgia. There are multiple topical capsaicin formulations available, including creams and solutions, indicated for temporary analgesia in muscle and join pain as well as neuropathic pain. Polatuzumab vedotin pharmacodynamics: Polatuzumab vedotin is an anti-cancer agent that works to cause apoptosis in malignant B cells. In vitro, it exerted cytotoxic effects on most diffuse large B-cell lymphoma (DLBCL) cell lines: this effect was consistent across cell lines, regardless of the cell-of-origin subtypes and whether they harboured mutations in the CD79B gene or not. In mouse xenograft models, polatuzumab vedotin caused apoptosis and reduced proliferation of mature CD79b+ B-cell NHL cell lines. Polatuzumab vedotin can cause immunosuppression, including neutropenia and thrombocytopenia. Capsaicin pharmacodynamics: Capsaicin is a TRPV1 receptor agonist. TRPV1 is a trans-membrane receptor-ion channel complex activated by temperatures higher than 43 degrees Celsius, pH lower than 6, and endogenous lipids. When activated by a combination of these factors, the channel can transiently open and initiate depolarization due to the influx of calcium and sodium ions. Because TRPV1 is commonly expressed in A-delta and mostly C fibers, depolarization results in action potentials which send impulses to the brain and spinal cord. These impulses result in capsaicin effects of warming, tingling, itching, stinging, or burning. Capsaicin also causes more persistent activation of these receptors compared to the environmental agonists, resulting in a loss of response to many sensory stimuli, described as "defunctionalization". Capsaicin is associated with many enzymatic, cytoskeletal, and osmotic changes, as well as disruption of mitochondrial respiration, impairing nociceptor function for extended periods of time. The mechanism of action of Polatuzumab vedotin is that it Polatuzumab vedotin is an antibody-drug conjugate consisting of a CD79b-directed antibody, a microtubule-disrupting agent called monomethyl auristatin E (MMAE), and a cleavable linker that holds the components together. CD79 is a heterodimer composed of CD79a and CD79b. Responsible for signal transduction, CD79 forms a complex with the B cell receptor (BCR) and is almost exclusively expressed on B cells, including malignant B cells. Most importantly, CD79b gained increasing attention as a promising therapeutic target as it plays an essential role in BCR expression, transport, and functions such as B cell proliferation and differentiation. Once the antibody component binds to CD79b, polatuzumab vedotin is internalized, and lysosomal proteases cleave the linker to release MMAE in the cell. MMAE is a microtubule-disrupting anti-mitotic agent that exerts cytotoxic effects against malignant B cells. It binds to microtubules, inhibits mitosis by interfering with tubulin and tubulin polymerization, and induces apoptosis in dividing B cells. The mechanism of action of Capsaicin is that it Capsaicin has been shown to reduce the amount of substance P associated with inflammation - however this is not believed to be its main mechanism in the relief of pain. Capsaicin's mechanism of action is attributed to "defunctionalization" of nociceptor fibers by inducing a topical hypersensitivity reaction on the skin. This alteration in pain mechanisms is due to many of the following: temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fiber terminals. Polatuzumab vedotin absorption: After the first polatuzumab vedotin dose of 1. 8 mg/kg, the mean (± SD) Cmax of antibody-conjugated MMAE and unconjugated MMAE were 803 (± 233) ng/mL and 6. 82 (± 4. 73) ng/mL, respectively. The mean AUC inf of antibody-conjugated MMAE and unconjugated MMAE were 1860 (± 966) day x ng/mL and 52. 3 (± 18. 0) day x ng/mL, respectively. Capsaicin absorption: Oral: Following oral administration, capsaicin may be absorbed by a nonactive process from the stomach and whole intestine with an extent of absorption ranging between 50 and 90%, depending on the animal. The peak blood concentration can be reached within 1 hour following administration. Capsaicin may undergo minor metabolism in the small intestine epithelial cells post-absorption from the stomach into the small intestines. While oral pharmacokinetics information in humans is limited, ingestion of equipotent dose of 26. 6 mg of pure capsaicin, capsaicin was detected in the plasma after 10 minutes and the peak plasma concentration of 2. 47 ± 0. 13 ng/ml was reached at 47. 1 ± 2. 0 minutes. Systemic: Following intravenous or subcutaneous administration in animals, the concentrations in the brain and spinal cord were approximately 5-fold higher than that in blood and the concentration in the liver was approximately 3-fold higher than that in blood. Topical: Topical capsaicin in humans is rapidly and well absorbed through the skin, however systemic absorption following topical or transdermal administration is unlikely. For patients receiving the topical patch containing 179 mg of capsaicin, a population analysis was performed and plasma concentrations of capsaicin were fitted using a one-compartment model with first-order absorption and linear elimination. The mean peak plasma concentration was 1. 86 ng/mL but the maximum value observed in any patient was 17. 8 ng/mL. The volume of distribution of Polatuzumab vedotin is The estimated central volume of distribution of polatuzumab vedotin based on population PK analysis is 3. 15 L. No volume of distribution information is available for Capsaicin. Polatuzumab vedotin is MMAE is 71% to 77% bound to plasma proteins. Its blood-to-plasma ratio is 0. 79 to 0. 98, in vitro. bound to plasma proteins. No protein binding information is available for Capsaicin. Polatuzumab vedotin metabolism: Polatuzumab vedotin is expected to undergo catabolism into small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. MMAE is metabolized by CYP3A4/5. Capsaicin metabolism: Capsaicin metabolism after oral administration is unclear, however it is expected to undergo metabolism in the liver with minimal metabolism in the gut lumen. In vitro studies with human hepatic microsomes and S9 fragments indicate that capsaicin is rapidly metabolized, producing three major metabolites, 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin, whereas vanillin was a minor metabolite. It is proposed that cytochrome P450 (P450) enzymes may play some role in hepatic drug metabolism. In vitro studies of capsaicin in human skin suggest slow biotransformation with most capsaicin remaining unchanged. Polatuzumab vedotin is eliminated via Polatuzumab vedotin is predominantly excreted in feces, as well as in urine to some extent. Capsaicin is eliminated via It is proposed that capsaicin mainly undergoes renal excretion, as both the unchanged and glucuronide form. A small fraction of unchanged compound is excreted in the feces and urine. In vivo animal studies demonstrates that less than 10 % of an administered dose was found in faces after 48 h. The half-life of Polatuzumab vedotin is The terminal half-life of polatuzumab vedotin is approximately 12 days (95% CI: 8. 1 to 19. 5 days) at Cycle 6. The terminal half-life of unconjugated MMAE is approximately four days after the first dose of polatuzumab vedotin. The half-life of Capsaicin is Following oral ingestion of equipotent dose of 26. 6 mg of pure capsaicin, the half life was approximately 24. 9 ± 5. 0 min. Following topical application of 3% solution of capsaicin, the half-life of capsaicin was approximately 24 h. The mean population elimination half-life was 1. 64 h following application of a topical patch containing 179 mg of capsaicin. The clearance of Polatuzumab vedotin is The predicted clearance of polatuzumab vedotin is 0. 9 L/day. No clearance information is available for Capsaicin. Polatuzumab vedotin toxicity includes Data regarding overdoses and LD 50 are not readily available. Capsaicin toxicity includes Acute oral LD50 and dermal LD50 in mouse are 47. 2 mg/kg and >512 mg/kg, respectively. Capsaicin is shown to be mutagenic for bacteria and yeast. Capsaicin can cause serious irritation, conjunctivitis and lacrimation via contact with eyes. It induces a burning sensation and pain in case of contact with eyes and skin. As it is also irritating to the respiratory system, it causes lung irritation and coughing as well as bronchoconstriction. Other respiratory effects include laryngospasm, swelling of the larynx and lungs, chemical pneumonitis,respiratory arrest and central nervous system effects such as convulsions and excitement. In case of ingestion, gastrointestinal tract irritation may be observed along with a sensation of warmth or painful burning. Symptoms of systemic toxicity include disorientation, fear, loss of body motor control including diminished hand-eye coordination, hyperventilation, tachycardia, and pulmonary oedema. Careful early decontamination is recommended and medical intervention should be initiated for any life-threatening symptoms. In case of contact, individual must be removed from the source of exposure and the contacted skin and mucous membranes should be thoroughly washed with copious amounts of water. Brand names of Polatuzumab vedotin include Polivy. Brand names of Capsaicin include Capzasin Quick Relief, Capzasin-HP, Castiva Warming, Dendracin Neurodendraxcin, Lidopro, Medi-derm, Medi-derm With Lidocaine, Medrox, Qutenza, Rematex, Xoten-C, Zostrix. No synonyms are available for Polatuzumab vedotin. No synonyms are available for Capsaicin. Capsaicina Isodecenoic acid vanillylamide Polatuzumab vedotin summary: It is Polatuzumab vedotin is a CD79b antibody conjugate indicated to treat different types of large B-cell lymphoma. Capsaicin summary: It is Capsaicin is a topical analgesic agent used for the symptomatic relief of neuropathic pain associated with post-herpetic neuralgia, as well as other muscle and joint pain. Answer: The use of local anesthetics has been associated with the development of methemoglobinemia, a rare but serious and potentially fatal adverse effect. The concurrent use of local anesthetics and oxidizing agents such as antineoplastic agents may increase the risk of developing methemoglobinemia.

Polatuzumab vedotin

Drug A is Obinutuzumab. Drug B is Besilesomab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Obinutuzumab is combined with Besilesomab. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Obinutuzumab is indicated for Obinutuzumab is used as a combination treatment with chlorambucil to treat patients with untreated chronic lymphocytic leukemia. Besilesomab is indicated for Besilesomab is radiolabelled with sodium pertechnetate (Tc99m) solution to develop technetium (Tc99m) besilesomab solution. This solution is indicated in adults for scintigraphic imaging - in conjunction with other appropriate imaging modalities, when possible - in determining the location of inflammation/infection in peripheral bone in adults with suspected osteomyelitis. When utilized as such, this medicinal product is for diagnostic use only. Obinutuzumab pharmacodynamics: Obinutuzumab is more potent than rituximab in depleting B-cells, antitumor activity, and tumor regression. Besilesomab pharmacodynamics: In a study employing cryo-preserved human tissues using an indirect alkaline phosphatase anti-alkaline phosphatase technique, besilesomab antibody from hybridoma supernatants demonstrated staining to cytoplasmic, membranous, and interstitial areas of primary colon carcinoma tissue, to single granulocytic cells in normal human liver and lung and to a large proportion of granulocytic cells in normal human bone marrow but not to blood vessels or connective tissue. Additionally, the antibody also shows binding to the granulocytic cells of breast, kidney, parotid gland, pituitary, lymph nodes, and spleen tissues, as well as colonic, pancreatic, and some lung and breast carcinomas. The purified besilesomab antibody and the prepared kit subsequently bound similarly to granulocytes in normal bone marrow, lung, liver, spleen, and colorectal carcinomas. Furthermore, the prepared kit also produced some staining in some connective tissue fibres in normal lung, some muscle fibres in normal colon, and in liver parenchymal cells. In general however, besilesomab does not bind significantly to blood vessels and connective tissue. The mechanism of action of Obinutuzumab is that it In contrast to rituximab, which is a classic type I CD20 antibody, obinutuzumab binds to type II CD20 antibodies. This allows obinutuzumab to have a much higher induction of antibody-dependant cytotoxicity and a higher direct cytotoxic effect than the classic CD20 antibodies. The mechanism of action of Besilesomab is that it Nonspecific cross-reacting antigens (NCA) is the name of a collection of highly glycosylated bacterial binding receptors expressed on human granulocytes and other tissues. In particular, these glycoprotein receptors are members of the immunoglobulin supergene family and are related structurally to carcinoembryonic antigen (CEA). CEA is found naturally in the human body and its expression may be increased in both cancer and non-cancerous (benign) circumstances. Besilesomab is subsequently a murine immunoglobulin monoclonal antibody of IgG1 isotype designed to recognise and bind specifically to NCA-95, or nonspecific cross-reacting antigen 95, an epitope found expressed on the cell membranes of granulocytes and granulocyte precursors. When radiolabelled with sodium pertechnetate (Tc99m) solution to develop technetium (Tc99m) besilesomab solution, this radiolabelled medicine is injected into patients where the monoclonal antibody carries it to target CEA on target granulocytes. When large numbers of CEA expressing granulocytes gather to the site of an infection, the radioactive monoclonal antibodies will also accumulate at such sites, where it can be detected by diagnostic scanning. The resultant images show where the radioactive besilesomab has accumulated, locating areas affected by osteomyelitis, infection, or inflammation. Furthermore, it is believed that the besilesomab accumulation is predominantly passive (via increased vascular permeability) and only partially active (via migration of human granulocytes carrying besilesomab to the infection/inflammation location) since only 10% to 20% of the injected radio-diagnostic agent binds in vivo to human circulating granulocytes. Specific binding of besilesomab to activated granulocytes that have already migrated to sites of infection/inflammation might be the primary part of the detection signal. Obinutuzumab absorption: Obinutuzumab is administered intravenously, so its absorption is 100%. Besilesomab absorption: As the diagnostic agent is administered intravenously, it is expected that the bioavailability is 100%. Approximately six hours after injection, about 1. 5% of the whole body radioactivity is detected in the liver while about 3. 0% is found in the spleen. Observations twenty-four hours after injection demonstrate percentages of radioactivity of 1. 6% in the liver and 2. 3% in the spleen. However, non pathological, unusual accumulations of the radioactive agent can be detected in the spleen (up to 6% of patients), in the bowel (up to 4% of patients), in the liver and bone marrow (up to 3% of patients), and in the thyroid and kidneys (up to 2% of patients). The volume of distribution of Obinutuzumab is Obinutuzumab has a volume of distribution of about 3. 8 L. The volume of distribution of Besilesomab is In the besilesomab clinical trial Study 7D-101SZ-A, volumes of distribution were determined as approximately 4L - which was close to the plasma volume - in the central compartment, whether calculated from plasma radioactivity or from intact monoclonal antibody concentrations; the peripheral compartment was somewhat greater, at about 6L for both methods. Obinutuzumab is Obinutuzumab does not bind to plasma proteins. bound to plasma proteins. Besilesomab is Studies demonstrate that prepared kit besilesomab binds up to 97. 45% and 96. 58% of peripheral blood granulocytes in males and females respectively and less than 5% of other peripheral blood cells. Moreover, no significant binding of the antibody to other human peripheral blood cells like erythrocytes, platelets, lymphocytes, and monocytes was observed. As well, besilesomab demonstrates no cross-reactivity with human platelets. bound to plasma proteins. Obinutuzumab metabolism: Obinutuzumab is not metabolized by the liver. Besilesomab metabolism: The besilesomab antibody is mainly metabolized via hepatic clearance into amino acids. Nevertheless, liver uptake of radioactivity was observed to be minimal under trial conditions and liver impairment is considered unlikely to affect besilesomab metabolism and elimination in any clinically significant manner. The total blood radioactivity occurring from the administration of besilesomab is generally the result of the contribution of radioactive intact labelled antibody and other radioactive moieties like metabolized antibody fragments, smaller radiometabolites, and free technetium (Tc99m). Obinutuzumab is eliminated via The route of elimination of obinutuzumab was not indicated (FDA label). Besilesomab is eliminated via Measurement of radioactivity levels in urine shows that up to 14% of the administered activity is excreted via the bladder during the 24 h post-injection period. Low renal clearance activity (of 0. 2 L/h for a glomerular filtration rate of approximately 7 L/h) also suggests that the kidney is not the primary route of besilesomab elimination. Additionally, over 30 hours rat pharmacokinetic studies also similarly demonstrated that 31-34% of the radioactivity was excreted in the urine and only 7-13% in the faeces. The faecal elimination was observed primarily from the 17h time period onward. Furthermore, while radioactivity associated with intact antibody tends to stay in the vascular compartment for a long time, metabolized radioactive fragments, small radio-metabolites, and free pertechnetate (Tc99m) clears quickly from blood and will accumulate in the kidneys and further in the urine. In all besilesomab studies to date, approximately 14% of the injected radioactivity was recovered in the urine, which was only collected for 24 hours after administration. The half-life of Obinutuzumab is The half life of obinutuzumab is 28. 4 days. The half-life of Besilesomab is Whole blood concentration-time radioactivity curves show a two-phase course, which can be subdivided into an early phase (0-2 h) and a late phase (5-24 h). After correcting for the decay of radionuclide, the calculated half-life of the early phase is approximately 0. 5 h while the late phase demonstrates a calculated half-life of 16 h. The terminal half-life in man is estimated to be approximately 23 h. The clearance of Obinutuzumab is The clearance of obinutuzumab is 0. 09L/day. The clearance of Besilesomab is Once administered into the body, prepared technetium (Tc99m) besilesomab can be metabolized into free amino acids, smaller radioactive fragments, or even free pertechnetate (Tc99m). The besilesomab clinical study 7D-101SZ-A consequently reports separate estimated clearance rates of 0. 322 L/h and 0. 242 L/h that were calculated using monitored plasma radioactivity and from monitored intact monoclonal antibody concentrations, respectively. Obinutuzumab toxicity includes The most serious toxicities observed with obinutuzumab are Hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML). HBV reactivation can occur with all anti-CD20 antibodies and can result in hepatic failure, fulminant hepatitis, and death. PML occurs as a result of JC virus infection and can be fatal as well. Other common but less serious adverse reactions include infusion reactions (pre-treat with glucocorticoids, acetaminophen, and anti-histamine to prevent this), neutropenia, thrombocytopenia, and Tumor Lysis Syndrome (TLS) (pre-treat patients, especially with a high lymphocyte count and/or a high tumor burden, with anti-hyperuricemics and hydration). It is also recommended to NOT administer live virus vaccinations prior to or during obinutuzumab treatment. Besilesomab toxicity includes The most commonly reported adverse reaction associated with the use of besilesomab is the development of Human Anti-Mouse Antibodies (HAMA) after a single administration. Patients who have developed HAMA may potentially have a higher risk for hypersensitivity reactions. Screening for possible previous exposure to murine monoclonal antibodies and tests for the presence of HAMA in prospective patients should be made prior to administrating besilesomab. Moreover, because the incidence of developing HAMA appears to be dose related with besilesomab, the recommended dosage is restricted to no more than 250 micrograms of antibody per injection. Patients who are HAMA positive are consequently contraindicated from using besilesomab. Hypersensitivity to besilesomab or to any other murine antibodies or to any of the excipients associated with the active besilesomab radio-diagnostic agent is subsequently a contraindication. Some patients have also reported hypotension as a common adverse reaction. As exposure to ionizing radiation is linked with cancer induction and a potential for developing hereditary defects, the use of radio-diagnostic besilesomab in pregnant women is considered a formal contraindication. If in doubt about a woman's potential pregnancy, alternative techniques to not using ionizing radiation should be considered and/or offered instead to the patient. Moreover, although it is not known if besilesomab is excreted in human milk, the potential risk to a breast-fed child cannot be excluded. Furthermore, while consideration should be given to the possibility of perhaps delaying the administration of radionuclide agents until the mother has ceased breastfeeding or perhaps certainly choosing alternative radoopharmaceuticals with more appropriate secretion activity, if the use of besilesomab is absolutely necessary then the mother's breastfeeding should be stopped for three days and any expressed feeds during that time discarded. The time period of three days corresponds to 10 half-lives of technetium (Tc99m)(60 hours). At that time, the remaining activity represents about 1/1000 of the initial activity in the body. In general, close contact with infants and pregnant women should be restricted for patients who have been administered besilesomab during the first 12 hours after the injection. Since besilesomab contains sorbitol, patients having any rare hereditary conditions of fructose intolerance should not be administered this medicine. Because no sufficient data regarding the safety and efficacy of using besilesomab in children below the age of 18 years exists, the use of besilesomab in this patient population is not recommended. Even though data regarding the repeated dosing of besilesomab is extremely limited, the use of besilesomab should only be used once in a patient's lifetime. Other medicines that can inhibit inflammation or affect the hematopoietic system (like antibiotics and corticosteroids) can lead to false negative results. Such agents should therefore not be administered together with, or a short time before the injection of besilesomab. Preclinical data obtained with the non-radioactive compound revealed no special hazard for humans based on conventional studies of safety pharmacology, single-dose and repeated dose toxicity, although antimurine antibodies were found in all dose groups (including controls) in a repeated-dose study in monkeys. Genotoxicity studies conducted to test for potentially genotoxic impurities were also negative. Long-term carcinogenicity studies and toxicity to reproduction have not yet been carried out. Brand names of Obinutuzumab include Gazyva. Brand names of Besilesomab include No brand names available. No synonyms are available for Obinutuzumab. No synonyms are available for Besilesomab. Obinutuzumab summary: It is Obinutuzumab is an antineoplastic CD20 antibody used to treat untreated chronic lymphocytic leukemia in combination with chlorambucil. Besilesomab summary: It is Besilesomab is a monoclonal antibody bound to technetium-99 used to find infection and inflammation in patients with suspected osteomyelitis. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Obinutuzumab

Drug A is Belatacept. Drug B is Fluorouracil. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Fluorouracil is combined with Belatacept. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Belatacept is indicated for prophylaxis of organ rejection. It is also used concomitantly with basiliximumab for induction therapy, mycophenolate, and corticosteriods in kidney transplant recepients that are seropositive for the Epstein-Barr virus. Fluorouracil is indicated for the topical treatment of multiple actinic or solar keratoses. In the 5% strength it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas, renal cell, and carcinoid. Belatacept pharmacodynamics: Belatacept binds to CD86 with a 4-fold higher affinity than abatacept. It also binds to CD80 with a 2-fold higher affinity than abatacept. It was observed in non-human primates that belatacept prolongs graft survival due to a decrease in antibody production against the donor organ. Furthermore, belatacept also inhibits the primary humoral immune response which is indicated by the decrease in post-transplant levels of IgG, IgM, and IgA. The magnitude of this effect is more significant in belatacept than it is in cyclosporine. Fluorouracil pharmacodynamics: Fluorouracil is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division. Fluorouracil blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand. The mechanism of action of Belatacept is that it Belatacept is a fusion protein in which the Fc portion of human IgG1 is attached onto the extracellular portion of human CTLA-4 (CD152). Belatacept specifically binds to CD80 and CD86 receptors that are found on the antigen-presenting cell (B cells, macrophages, dendritic cells) to block selective T-cell lymphocyte costimulation. CD80 and CD86 would normally act as the ligands to the CD28 receptor T-cells in which this interaction triggers the activation of T lymphocytes. However in the presence of belatacept, because the extracellular CTLA-4 component binds to CD28 with higher affinity than CD80 or CD86, T lymphyocyte anergy, a state of antigen specific tolerance, occurs instead. The T cell is also no longer able to respond to their antigen. The mechanism of action of Fluorouracil is that it The precise mechanism of action has not been fully determined, but the main mechanism of fluorouracil is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. Fluorouracil can also be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis. Belatacept absorption: Following multiple intravenous doses of an initial 10 mg/kg dose and followed by a maintenance dose of 5 mg/kg in kidney transplant recipients, these are the following pharmacokinetic parameters:. Cmax, 10 mg/kg = 247 µg/mL; Cmax, 5 mg/kg = 139 µg/mL; AUC, 10 mg/kg = 22,252 µg · h/mL; AUC, 5 mg/kg = 14,090 µg · h/mL; Belatacept had linear and dose-dependent pharmacokinetic profile. Fluorouracil absorption: 28-100%. The volume of distribution of Belatacept is Vd, steady state, transplant patients, 10 mg/kg = 0. 11 L/kg;. Vd, steady state, transplant patients, 5 mg/kg = 0. 12 L/kg No volume of distribution information is available for Fluorouracil. No protein binding information is available for Belatacept. Fluorouracil is 8-12% bound to plasma proteins. Belatacept metabolism: The cytochrome P450 enzyme system or uridine diphosphate-glucuronosyltransferases are not expected to be involved with the metabolism of belatacept. Because the drug is a protein, belatacept is degraded into smaller peptides and amino acids by proteolytic enzymes. Fluorouracil metabolism: Hepatic. The catabolic metabolism of fluorouracil results in degradation products ( e. g., CO2, urea and α-fluoro-ß-alanine) which are inactive. Belatacept is eliminated via No route of elimination available. Fluorouracil is eliminated via Seven percent to 20% of the parent drug is excreted unchanged in the urine in 6 hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver. The half-life of Belatacept is Mean terminal elimination half-life:. 10 mg/kg, kidney transplant recipients= 9. 8 days; 5 mg/kg, kidney transplant recipient = 8. 2 days The half-life of Fluorouracil is 10-20 minutes. The clearance of Belatacept is Increased body weight may increase the clearance rate of belatacept. Mean systemic clearance is. 10 mg/kg, kidney transplant recipients= 0. 49 mL/h/kg; 5 mg/kg, kidney transplant recipient = 0. 51 mL/h/kg. No clearance information is available for Fluorouracil. No toxicity information is available for Belatacept. Fluorouracil toxicity includes LD 50 =230mg/kg (orally in mice). Brand names of Belatacept include Nulojix. Brand names of Fluorouracil include Actikerall, Carac, Efudex, Fluoroplex, Tolak. No synonyms are available for Belatacept. No synonyms are available for Fluorouracil. 5-Fluorouracil 5-Fluracil 5-FU Fluoro Uracil Fluorouracil Fluorouracilo Fluorouracilum Fluouracil Belatacept summary: It is Belatacept is a selective T-cell costimulation blocker used in the prophylaxis of organ rejection in adult patients receiving a kidney transplant. Fluorouracil summary: It is Fluorouracil is a pyrimidine analog used to treat basal cell carcinomas, and as an injection in palliative cancer treatment. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Belatacept

Drug A is Acalabrutinib. Drug B is Apremilast. The severity of the interaction is major. The metabolism of Acalabrutinib can be increased when combined with Apremilast. The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. Acalabrutinib is indicated for Acalabrutinib is currently indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. It has also been recently approved for chronic lymphocytic leukemia and small lymphocytic lymphoma. Apremilast is indicated for Apremilast is indicated for the treatment of adults with active psoriatic arthritis and adults with oral ulcers associated with Behcet's Disease. In addition, apremilast is indicated for the treatment of plaque psoriasis, of any severity, in adult patients who are candidates for phototherapy or systemic therapy. Acalabrutinib pharmacodynamics: Acalabrutinib is a Bruton Tyrosine Kinase inhibitor that prevents the proliferation, trafficking, chemotaxis, and adhesion of B cells. It is taken every 12 hours and can cause other effects such as atrial fibrillation, other malignancies, cytopenia, hemorrhage, and infection. Apremilast pharmacodynamics: Apremilast reduces but does not completely inhibit various inflammatory cytokines such as IL-1α, IL-6, IL-8, IL-10 MCP-1, MIP-1β, MMP-3, and TNF-α, relieving the symptoms of psoriasis and Behcet's disease, which are caused by an increase in these inflammatory mediators. This drug has also been proven to be effective in relieving the pain associated with oral ulcers in Behcet's disease. Apremilast may cause unwanted weight loss and worsen depression, leading to suicidal thoughts or actions. It is advisable to monitor for symptoms of depression and seek medical attention if they occur, especially in patients with pre-existing depression. The need for apremilast should be carefully assessed along with the risk of worsening depression and suicide. If weight loss occurs, the degree of weight loss should be evaluated, and consideration should be made for the possible discontinuation of apremilast. The mechanism of action of Acalabrutinib is that it Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. Subsequently, relapse is common in MCL patients and ultimately represents disease progression. Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas are the body's own B-lymphocytes (B-cells). Bruton Tyrosine Kinase (BTK) is a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Acalabrutinib is a small molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity. As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor, acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates highter selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1. In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects - in theory - because of the drug's minimized off target effects. The mechanism of action of Apremilast is that it The full mechanism of action of this drug is not fully established, however, it is known that apremilast is an inhibitor of phosphodiesterase 4 (PDE4), which mediates the activity of cyclic adenosine monophosphate (cAMP), a second messenger. The inhibition of PDE4 by apremilast leads to increased intracellular cAMP levels. An increase in cAMP results in the suppression of inflammation by decreasing the expression of TNF-α, IL-17, IL-23, and other inflammatory mediators. The above inflammatory mediators have been implicated in various psoriatic conditions as well as Behcet's disease, leading to their undesirable inflammatory symptoms such as mouth ulcers, skin lesions, and arthritis. Apremilast administration leads to a cascade which eventually decreases the levels of the above mediators, relieving inflammatory symptoms. Acalabrutinib absorption: The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0. 75 hours. Apremilast absorption: An oral dose of apremilast is well-absorbed and the absolute bioavailability is approximately 73%. Tmax is approximately 2. 5 hours and Cmax has been reported to be approximately 584 ng/mL in one pharmacokinetic study. Food intake does not appear to affect apremilast absorption. The volume of distribution of Acalabrutinib is The mean steady-state volume of distribution is approximately 34 L. The volume of distribution of Apremilast is The average apparent volume of distribution (Vd) is about 87 L, suggesting that apremilast is distributed in the extravascular compartment. Acalabrutinib is Reversible binding of acalabrutinib to human plasma protein is approximately 97. 5%. The in vitro mean blood-to-plasma ratio is about 0. 7. In vitro experiments at physiologic concentrations show that acalabrutinib can be 93. 7% bound to human serum albumin and 41. 1% bound to alpha-1-acid glycoprotein. bound to plasma proteins. Apremilast is The plasma protein binding of apremilast is about 68%. bound to plasma proteins. Acalabrutinib metabolism: Acalabrutinib is mainly metabolized by CYP3A enzymes. ACP-5862 is identified to be the major active metabolite in plasma with a geometric mean exposure (AUC) that is about 2-3 times greater than the exposure of acalabrutinib. ACP-5862 is about 50% less potent than acalabrutinib in regards to the inhibition of BTK. Apremilast metabolism: Apremilast is heavily metabolized by various pathways, which include oxidation, hydrolysis, in addition to conjugation. About 23 metabolites are produced from its metabolism. The CYP3A4 primarily mediates the oxidative metabolism of this drug, with smaller contributions from CYP1A2 and CYP2A6 enzymes. The main metabolite of apremilast, M12, is an inactive glucuronide conjugate form of the O-demethylated drug. Some other major metabolites, M14 and M16, are significantly less active in the inhibition of PDE4 and inflammatory mediators than their parent drug, apremilast. After an oral dose, unchanged apremilast (45%) and the inactive metabolite, O-desmethyl apremilast glucuronide (39%) are found in the plasma. Minor metabolites M7 and M17 are active, but are only present in about 2% or less of apremilast concentrations, and likely not significant contributors to the actions of apremilast. Acalabrutinib is eliminated via After administration of a single 100 mg radiolabelled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine. An irradiated dose of acalabrutinib was 34. 7% recovered as the metabolite ACP-5862; 8. 6% was recovered as unchanged acalabrutinub; 10. 8 was recovered as a mixture of the M7, M8, M9, M10, and M11 metabolites; 5. 9% was the M25 metabolite; 2. 5% was recovered as the M3 metabolite. Apremilast is eliminated via Only 3% and 7% of an apremilast dose are detected in the urine and feces as unchanged drug, respectively, indicating extensive metabolism and high absorption. The half-life of Acalabrutinib is After administering a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life of the drug was found to be 0. 9 (with a range of 0. 6 to 2. 8) hours. The half-life of the active metabolite, ACP-5862, is about 6. 9 hours. The half-life of Apremilast is The average elimination half-life of this drug ranges from 6-9 hours. The clearance of Acalabrutinib is Acalabrutinib's mean apparent oral clearance (CL/F) is observed to be 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis. The clearance of Apremilast is In healthy patients, the plasma clearance of apremilast is about 10 L/hour. Acalabrutinib toxicity includes Data regarding the toxicity of acalabrutinib is not readily available. Apremilast toxicity includes The oral LD50 in mice was greater than 2000 mg/kg in mice. In rats, oral LD50 was 2000 mg/kg males and 300 mg/kg in females. Overdose information In healthy subjects receiving a maximum dose of 100 mg (given as 50 mg twice daily) for about 5 days, no significant toxicity was observed. In cases of an overdose, supportive and symptomatic treatment should be administered. Contact the local poison control center for the most recent overdose management for apremilast. Brand names of Acalabrutinib include Calquence. Brand names of Apremilast include Otezla. No synonyms are available for Acalabrutinib. No synonyms are available for Apremilast. Apremilast Apremilastum Acalabrutinib summary: It is Acalabrutinib is a Bruton tyrosine kinase inhibitor used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Apremilast summary: It is Apremilast is a non-steroidal medication used for the treatment of inflammatory conditions such as psoriasis and psoriatic arthritis. Answer: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index.

Acalabrutinib

Drug A is Octreotide. Drug B is Tolvaptan. The severity of the interaction is moderate. The serum concentration of Tolvaptan can be increased when it is combined with Octreotide. Octreotide suppresses growth hormone, which may result in the suppression of CYP enzymes 1 required to metabolize drugs with a narrow therapeutic index. These drugs must be maintained within a specific serum concentration range in order to be safe and effective. Reductions in their metabolism due to a decrease in metabolic enzymes can increase exposure and adverse effects related to their use. Octreotide is indicated for Octreotide by injection is used for the treatment of acromegaly and the reduction of flushing and diarrhea symptoms related to carcinoid tumors and/or vasoactive intestinal peptide (VIPoma) tumors. The delayed-release oral formulation is used for the long-term treatment of acromegaly in patients who tolerate and respond adequately to injectable octreotide and lanreotide. Tolvaptan is indicated for Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and cirrhosis. Octreotide pharmacodynamics: Octreotide mimics the naturally occurring hormone known as somatostatin. Like somatostatin, it demonstrates activity against growth hormone and glucagon, treating the disordered tissue growth and insulin regulation in patients with acromegaly. In addition, octreotide relieves the flushing and diarrhea associated with gastrointestinal tumors by reducing splanchnic blood flow and various gastrointestinal hormones associated with diarrhea. Product labeling warns that octreotide may reduce gallbladder contractility, bile secretion, and the release of thyroid-stimulating hormone (TSH) in healthy volunteers. In addition, reports of decreased vitamin B12 in patients treated with octreotide have been made. Ensure to monitor vitamin B12 levels in patients taking octreotide. Tolvaptan pharmacodynamics: Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan. Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours. The magnitude of serum sodium and osmolality change increases with escalating doses. Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan. The affinity for V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 receptors. The mechanism of action of Octreotide is that it Octreotide binds to somatostatin receptors coupled to phospholipase C through G proteins and leads to smooth muscle contraction in the blood vessels. Downstream effects that stimulate phospholipase C, the production of 1, 4,5-inositol triphosphate, and action on the L-type calcium channels lead to the inhibition of growth hormone, treating the various growth-hormone and metabolic effects of acromegaly. Octreotide's suppression of luteinizing hormone (LH), reduction in splanchnic blood flow, and inhibition of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide provide relief for the gastrointestinal and flushing symptoms of carcinoid and/or VIPoma tumors. The mechanism of action of Tolvaptan is that it Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls thus preventing water absorption. This action ultimately results in an increase in urine volume, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin. Octreotide absorption: After a subcutaneous dose, octreotide is absorbed completely upon administration. After the administration of an oral delayed-release capsule, peak concentrations were found to be 33% lower than after subcutaneous administration. The Cmax was attained at 1. 67–2. 5 hours after oral administration versus 30 minutes for the subcutaneous route. At 20 mg twice a day in patients with acromegaly, peak concentration was 2. 5 mg/nL versus 5. 30 ng/mL at 40 mg twice a day. AUC increases in proportion with the dose, regardless of the route. Tolvaptan absorption: Tmax, Healthy subjects: 2 - 4 hours;. Cmax, Healthy subjects, 30 mg is 374 ng/mL;. Cmax, Healthy subjects, 90 mg is 418 ng/mL;. Cmax, heart failure patients, 30 mg is 460 ng/mL;. Cmax, heart failure patients, 90 mg is 723 ng/mL;. AUC(0-24 hours), 60 mg is 3. 71 μg·h/mL;. AUC(∞), 60 mg is 4. 55 μg·h/mL;. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Food does not impact the bioavailability of tolvaptan. The volume of distribution of Octreotide is In a pharmacokinetic study, the volume of distribution was 13. 6 L in healthy volunteers. One pharmacokinetic study revealed a volume of distribution ranging from 18. 1-30. 4L after intravenous administration in healthy volunteers. The volume of distribution of Tolvaptan is Healthy subjects: 3L/kg; slightly higher in heart failure patients. Octreotide is Approximately 65% of the dose is bound in the plasma to lipoproteins and albumin. bound to plasma proteins. Tolvaptan is 99% bound to plasma proteins. Octreotide metabolism: Octreotide has been reported to be heavily metabolized in the liver. Tolvaptan metabolism: Metabolism exclusively by CYP3A4 enzyme in the liver. Metabolites are inactive. Octreotide is eliminated via About 32% of an oral octreotide dose is excreted into the urine and 30-40% is excreted by the liver into the feces. About 11% of the unchanged parent drug is found in the urine, and 2% of the unchanged parent drug can be recovered in the feces. Tolvaptan is eliminated via Fecal- very little renal elimination (<1% is excreted unchanged in the urine). The half-life of Octreotide is After a subcutaneous dose, the plasma half-life is estimated to be 0. 2 hours. The average elimination half-lives for subcutaneous and oral administration ranged from 2. 3 - 2. 7 hours and did not differ significantly. One pharmacokinetic study revealed a plasma half-life ranging from 72-113 minutes. The half-life of Tolvaptan is Terminal half life, oral dose = 12 hours. The clearance of Octreotide is The total body clearance of octreotide is 7-10 L/h. One pharmacokinetic study revealed a total body clearance of 11. 4 L/h. The clearance of Tolvaptan is 4 mL/min/kg (post-oral dosing). Octreotide toxicity includes There is limited information regarding cases of octreotide overdose aside from case reports of an overdose with injectable octreotide. The dose ranged from 2. 4 mg/day to 6 mg/day administered by continuous infusion or subcutaneous administration of 1. 5 mg three times daily. Effects of an overdose with octreotide may include hypotension, brain hypoxia, arrhythmia, cardiac arrest, lactic acidosis, pancreatitis, hepatomegaly, diarrhea, flushing, lethargy, and weakness. Tolvaptan toxicity includes The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia. Brand names of Octreotide include Bynfezia, Mycapssa, Sandostatin. Brand names of Tolvaptan include Jinarc, Jynarque 45/15 Carton, Samsca. No synonyms are available for Octreotide. No synonyms are available for Tolvaptan. Octreotide summary: It is Octreotide is a peptide drug used to treat acromegaly as well as diarrhea associated with metastatic carcinoid tumors and vasoactive intestinal peptide secreting tumors. Tolvaptan summary: It is Tolvaptan is a selective vasopressin V2-receptor antagonist to slow kidney function decline in patients at risk for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Also used to treat hypervolemic and euvolemic hyponatremia. Answer: Octreotide suppresses growth hormone, which may result in the suppression of CYP enzymes 1 required to metabolize drugs with a narrow therapeutic index. These drugs must be maintained within a specific serum concentration range in order to be safe and effective. Reductions in their metabolism due to a decrease in metabolic enzymes can increase exposure and adverse effects related to their use.

Octreotide

Drug A is Antihemophilic factor (recombinant), PEGylated. Drug B is Cimetidine. The severity of the interaction is minor. Cimetidine may decrease the excretion rate of Antihemophilic factor (recombinant), PEGylated which could result in a higher serum level. The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes, they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. Antihemophilic factor (recombinant), PEGylated is indicated for the management of hemophilia A (congenital factor VIII deficiency),. This medication is a human antihemophilic factor indicated in adolescent and adult patients (12 years and older) with hemophilia A (congenital factor VIII deficiency). It is also used for on-demand treatment and control of bleeding and routine prophylaxis of bleeding episodes. It is not indicated for the treatment of von Willebrand disease. Cimetidine is indicated for Cimetidine is indicated to reduce gastric acid secretion and to treat the following disease states: duodenal ulcers, non-malignant gastric ulcers, gastroesophageal reflux disease, and pathological hypersecretion associated with Zollinger-Ellison Syndrome, systemic mastocytosis, and multiple endocrine adenomas. It is indicated for prophylaxis of recurrent gastric or duodenal ulcers, as adjunctive therapy in the management of cystic fibrosis in children, and to treat NSAID induced lesions and gastrointestinal symptoms. Antihemophilic factor (recombinant), PEGylated pharmacodynamics: This drug temporarily replaces the missing coagulation factor VIII, required for effective hemostasis in patients with congenital hemophilia A. Hemophilia A patients have a deficiency of factor VIII, resulting in a prolonged, patient plasma clotting time as demonstrated by the activated partial thromboplastin time (aPTT). Treatment with recombinant factor VIII normalizes the aPTT. Hemophilia A is a sex-linked hereditary disorder of blood coagulation caused by decreased levels of Factor VIII activity, resulting in severe bleeding into the joints, muscles or internal organs, spontaneously/as a result of trauma,. Cimetidine pharmacodynamics: Cimetidine is a histamine H 2 -receptor antagonist. It reduces basal and nocturnal gastric acid secretion and a reduction in gastric volume, acidity, and amount of gastric acid released in response to stimuli including food, caffeine, insulin, betazole, or pentagastrin. It is used to treat gastrointestinal disorders such as gastric or duodenal ulcer, gastroesophageal reflux disease, and pathological hypersecretory conditions. Cimetidine inhibits many of the isoenzymes of the hepatic CYP450 enzyme system. Other actions of Cimetidine include an increase in gastric bacterial flora such as nitrate-reducing organisms. The mechanism of action of Antihemophilic factor (recombinant), PEGylated is that it PEG with Factor VIII effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce the susceptibility of this molecule to proteolytic degradation. It is also believed that PEGylation alters the surface charge of the protein that inhibits receptor-mediated clearance. This drug reduces binding to the LRP1 receptor, which normally clears factor VIII from the circulation,. The plasma levels of Factor VIII are increased with replacement therapy, which allows for a temporary correction of the factor deficiency, thus a correction of the bleeding tendency. The mechanism of action of Cimetidine is that it Cimetidine binds to an H 2 -receptor located on the basolateral membrane of the gastric parietal cell, blocking histamine effects. This competitive inhibition results in reduced gastric acid secretion and a reduction in gastric volume and acidity. Antihemophilic factor (recombinant), PEGylated absorption: AUC0-Inf [IU·h/dL]: 1642 ± 752 in children aged 12 to <18 years 2264 ± 729 in adults ≥18 years. Cimetidine absorption: Two peak plasma concentrations are often observed after oral administration of cimetidine, likely as a result of discontinuous absorption in the gastrointestinal tract. In healthy patients, the absolute bioavailability of cimetidine is approximately 60%; however, the bioavailability can be as high as 70% in patients with peptic ulcer disease. Overall, rates of bioavailability are much more variable in patients with peptic ulcer disease. The volume of distribution of Antihemophilic factor (recombinant), PEGylated is At steady state: 0. 56 ± 0. 18 dL/Kg in children aged 12 to <18 years 0. 43 ± 0. 11 dL/kg in adults aged ≥18 years. The volume of distribution of Cimetidine is The volume of distribution of cimetidine is reported to be 1 L/kg. No protein binding information is available for Antihemophilic factor (recombinant), PEGylated. Cimetidine is In humans, approximately 22. 5% of cimetidine is plasma protein bound. bound to plasma proteins. No metabolism information is available for Antihemophilic factor (recombinant), PEGylated. Cimetidine metabolism: After intravenous administration of cimetidine, the majority of the parent drug (58-77%) is eliminated unchanged in the urine. Cimetidine’s primary metabolite is cimetidine sulfoxide and represents an estimated 10-15% of total elimination. Researchers have also identified a minor cimetidine metabolite with a hydroxylated methyl group on the imidazole ring which represents only 4% of total elimination. Both cytochrome P450 enzymes and flavin-containing monooxygenases are implicated in the metabolism of cimetidine, although it is unclear which specific enzymes are involved. Cimetidine is a well known enzyme inhibitor and may impair the metabolism of certain co-administered medications. Antihemophilic factor (recombinant), PEGylated is eliminated via No route of elimination available. Cimetidine is eliminated via Cimetidine is excreted primarily in the urine. The half-life of Antihemophilic factor (recombinant), PEGylated is 14. 69 ± 3. 79h for adults aged ≥18 years 13. 43 ± 4. 05 for children 12 to <18 years. The half-life of Cimetidine is Cimetidine's half-life is estimated to be around 2 hours. The clearance of Antihemophilic factor (recombinant), PEGylated is 2. 27 ± 0. 84 for adults ≥18 years 3. 87 ± 3. 31 for children 12 to <18 years. The clearance of Cimetidine is Cimetidine's reported systemic clearance value is approximately 500-600 ml/min. Antihemophilic factor (recombinant), PEGylated toxicity includes Common adverse reactions reported in ≥1% of subjects in the clinical studies were headache and nausea. Cimetidine toxicity includes In the rare event of cimetidine overdose, it is vital to maintain the airway and cardiovascular status. The patient should be closely monitored and provided with symptomatic and supportive treatment as needed. Interventions such as gastric lavage and administration of activated charcoal may be initiated if deemed appropriate and necessary. Brand names of Antihemophilic factor (recombinant), PEGylated include Adynovate. Brand names of Cimetidine include Good Sense Heartburn Relief, Tagamet. No synonyms are available for Antihemophilic factor (recombinant), PEGylated. No synonyms are available for Cimetidine. Cimetidina Cimétidine Cimetidine Cimetidinum Antihemophilic factor (recombinant), PEGylated summary: It is No summary available. Cimetidine summary: It is Cimetidine is a histamine H2 receptor antagonist used to manage GERD, peptic ulcer disease, and indigestion. Answer: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

Antihemophilic factor (recombinant), PEGylated

Drug A is Bimekizumab. Drug B is Flutamide. The severity of the interaction is moderate. The metabolism of Flutamide can be increased when combined with Bimekizumab. The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. Bimekizumab is indicated for Bimekizumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Flutamide is indicated for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate. Bimekizumab pharmacodynamics: Bimekizumab exerts its pharmacologic effects by binding to and inhibiting one of the pro-inflammatory cytokines involved in psoriasis pathogenesis. It is administered once-monthly as a subcutaneous injection. Bimekizumab may increased the risk of infection, including upper respiratory tract infections and oral candidiasis. Any clinically important active infections should be resolved prior to therapy. In addition, the use of live vaccines during bimekizumab therapy is not recommended - ensure patients beginning therapy have completed all age appropriate immunizations prior to initiation. Flutamide pharmacodynamics: Flutamide is a nonsteroidal antiandrogen. In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e. g. castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration. The mechanism of action of Bimekizumab is that it The pathophysiology of psoriasis involves a dysregulation of the immune system and is facilitated by a variety of cytokines released by dendritic cells and T-helper cells. Plaque psoriasis, the most common subtype of psoriasis, is driven primarily by tumor necrosis factor-alpha (TNF-α) and interleukins 17 and 23 (IL-17 and IL-23), with the axis between these three cytokines integral to the maintenance phase of psoriasis. IL-17 acts through two separate mechanisms: the first, dependent on the cytoplasmic adaptor protein ACT1, involves the activation of NF-κB and the transcription of inflammatory genes. The second, independent of ACT1, involves the activation of the JAK/STAT signaling cascade, which leads to further transcription of pro-inflammatory proteins and continued psoriasis pathogenicity. Bimekizumab is a monoclonal antibody targeted against IL-17A, IL-17F, and a heterodimer of the two called IL-17AF. It blocks the interaction of these interleukins with their respective receptors, thus reducing psoriatic inflammation. The mechanism of action of Flutamide is that it Flutamide is a nonsteroidal antiandrogen that blocks the action of both endogenous and exogenous testosterone by binding to the androgen receptor. In addition Flutamide is a potent inhibitor of testosterone-stimulated prostatic DNA synthesis. Moreover, it is capable of inhibiting prostatic nuclear uptake of androgen. Bimekizumab absorption: In healthy volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70. 1%. Flutamide absorption: Rapidly and completely absorbed. The volume of distribution of Bimekizumab is In patients with plaque psoriasis, the median volume of distribution at steady-state was 11. 2 L. No volume of distribution information is available for Flutamide. No protein binding information is available for Bimekizumab. Flutamide is 94-96% bound to plasma proteins. Bimekizumab metabolism: As a monoclonal antibody, bimekizumab is likely degraded into smaller peptides and amino acids via catabolic processes. Flutamide metabolism: Flutamide is rapidly and extensively metabolized, with flutamide comprising only 2. 5% of plasma radioactivity 1 hour after administration. Bimekizumab is eliminated via No route of elimination available. Flutamide is eliminated via Flutamide and its metabolites are excreted mainly in the urine with only 4. 2% of a single dose excreted in the feces over 72 hours. The half-life of Bimekizumab is The mean terminal elimination half-life of bimekizumab in patients with plaque psoriasis was 23 days. The half-life of Flutamide is The plasma half-life for the alpha-hydroxylated metabolite of flutamide (an active metabolite) is approximately 6 hours. The clearance of Bimekizumab is The median apparent clearance of bimekuzmab in patients with plaque psoriasis was 0. 337 L/day. No clearance information is available for Flutamide. Bimekizumab toxicity includes Single doses of up to 640mg given both intravenously and subcutaneously have been administered in clinical studies without evidence of dose-limiting toxicities. If overdosage of bimekizumab is suspected, monitor the patient for adverse reactions and institute symptomatic treatment as clinically indicated. Flutamide toxicity includes In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis, and methemoglobinemia. Brand names of Bimekizumab include No brand names available. Brand names of Flutamide include Eulexin. No synonyms are available for Bimekizumab. No synonyms are available for Flutamide. Flutamida Flutamide Flutamidum NFBA Niftolid Niftolide Bimekizumab summary: It is Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment plaque psoriasis. Flutamide summary: It is Flutamide is an antiandrogen used for locally confined stage B2-C and D-2 metastatic prostate carcinoma. Answer: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates.

Bimekizumab

Drug A is Denosumab. Drug B is Sulfasalazine. The severity of the interaction is moderate. The risk or severity of adverse effects can be increased when Denosumab is combined with Sulfasalazine. The coadministration of denosumab with immunosuppressive agents poses a high risk of serious infection than with denosumab alone. 1,2,3 Denosumab is indicated for Denosumab under the brand name Prolia is indicated as a treatment for osteoporosis in menopausal women or men and glucocorticoid-induced osteoporosis in men and women at high risk of fracture. It is also used to increase bone mass in men at high risk for fractures receiving androgen deprivation therapy for nonmetastatic prostate cancer or women at high risk for fractures receiving adjuvant aromatase inhibitor therapy for breast cancer. Denosumab under the brand name Xgeva is indicated to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors and to treat giant cell tumors of bone in adults and skeletally mature adolescents and hypercalcemia of malignancy refractory to bisphosphonate therapy. Sulfasalazine is indicated for In the US, sulfasalazine is indicated to treat mild to moderate ulcerative colitis and to prolong the remission period between acute attacks of ulcerative colitis. Sulfasalazine is also indicated as an adjunct therapy in severe ulcerative colitis. For the delayed-release tablet formulation, sulfasalazine is also indicated to treat rheumatoid arthritis in pediatric patients who have responded inadequately to salicylates or other nonsteroidal anti-inflammatory drugs or polyarticular-course juvenile rheumatoid arthritis with the same patients' characteristics. Denosumab pharmacodynamics: In clinical studies, treatment with 60 mg of denosumab resulted in a reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0. 049 ng/mL) in 39% to 68% of patients 1 to 3 months after dosing of denosumab. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of denosumab on bone remodelling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by denosumab was similar to that observed in patients initiating denosumab treatment. Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i. e., osteocalcin and procollagen type 1 N-terminal peptide [P1NP]) were observed starting 1 month after the first dose of denosumab. After discontinuation of denosumab therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months. In patients with breast cancer and bone metastases, the median reduction in urinary N-terminal telopeptide corrected for creatinine (uNTx/Cr) was 82% within 1 week following initiation of denosumab 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 denosumab-treated patients. In a phase 3 study of patients with newly diagnosed multiple myeloma who received subcutaneous doses of denosumab 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing. Sulfasalazine pharmacodynamics: The mode of action of sulfasalazine or its metabolites, 5-aminosalicylic acid and sulfapyridine, is still under investigation but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver, and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of sulfasalazine, sulfapyridine, and 5-aminosalicylic acid have indicated that the major therapeutic action may reside in the 5-aminosalicylic acid moiety. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is unknown. The mechanism of action of Denosumab is that it Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. The mechanism of action of Sulfasalazine is that it Although the exact mechanism of action of sulfasalazine is not fully understood, it is thought to be mediated through the inhibition of various inflammatory molecules. Research have found that sulfasalazine and its metabolites, mesalazine and sulfapyridine, can inhibit leukotrienes and prostaglandins by blocking the cyclo-oxygenase and lipoxygenase pathway. Specific enzymes that were investigated include phospholipase A2, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX2), and arachidonate 5-lipoxygenase. Inhibitory activities on other non-arachidonic acid derivatives have also been observed, including PPAR gamma, NF-Kb, and IkappaB kinases alpha and beta. Denosumab absorption: In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered denosumab dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (Cmax ) was 6. 75 mcg/mL (standard deviation [SD] = 1. 89 mcg/mL). The median time to maximum denosumab concentration (Tmax ) was 10 days (range: 3 to 21 days). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg⋅day/mL (SD = 101 mcg⋅day/mL. No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months. Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years). After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) Cmax values in the serum and seminal fluid samples were 6170 (± 2070) and 100 (± 81. 9) ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels. The median (range) Tmax values in the serum and seminal fluid samples were 8. 0 (7. 9 to 21) and 21 (8. 0 to 49) days, respectively. Among the subjects, the highest denosumab concentration in the seminal fluid was 301 ng/mL at 22 days post-dose. On the first day of measurement (10 days post-dose), nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post-dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) seminal fluid concentration of 21. 1 (± 36. 5) ng/mL across all subjects (n = 12). In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach a steady state by month 6. In patients with giant cell tumor of bone, after administration of subcutaneous doses of 120 mg once every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day 8, 15, and one month after the first dose were 19. 0 (± 24. 1), 31. 6 (± 27. 3), 36. 4 (± 20. 6) mcg/mL,. respectively. Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23. 4 (± 12. 1) mcg/mL. Sulfasalazine absorption: Following oral administration of 1 g of sulfasalazine to 9 healthy males, less than 15% of a dose of sulfasalazine is absorbed as the parent drug. Detectable serum concentrations of sulfasalazine have been found in healthy subjects within 90 minutes after ingestion. Maximum concentrations of sulfasalazine occur between 3 and 12 hours post-ingestion, with the mean peak concentration (6 μg/mL) occurring at 6 hours. The volume of distribution of Denosumab is The central volume of distribution and volume of distribution at steady-state were calculated to be 2. 49 L/66 kg and 3. 5-7 L respectively. The volume of distribution of Sulfasalazine is Following intravenous injection, the calculated volume of distribution for sulfasalazine was 7. 5 ± 1. 6 L. Denosumab is No information is available on the protein binding of denosumab. bound to plasma proteins. Sulfasalazine is Sulfasalazine is highly bound to albumin (>99. 3%) while sulfapyridine is only about 70% bound to albumin. Acetylsulfapyridine, the principal metabolite of sulfapyridine, is approximately 90% bound to plasma proteins. bound to plasma proteins. Denosumab metabolism: No information is available on the metabolism of denosumab. Sulfasalazine metabolism: In the intestine, sulfasalazine is metabolized by intestinal bacteria to sulfapyridine and 5-aminosalicylic acid. Of the two species, sulfapyridine is relatively well absorbed from the intestine and highly metabolized, while 5-aminosalicylic acid is much less well absorbed. Approximately 15% of a dose of sulfasalazine is absorbed as the parent drug and is metabolized to some extent in the liver to the same two species. Sulfapyridine can also be metabolized to 5-hydroxysulfapyridine and N-acetyl-5-hydroxy sulfapyridine. 5-aminosalicylic acid is primarily metabolized in both the liver and intestine to N-acetyl-5 aminosalicylic acid via a non-acetylation phenotype-dependent route. Denosumab is eliminated via As an antibody, denosumab is likely cleared by the reticuloendothelial system with minimal renal filtration and excretion. Sulfasalazine is eliminated via Absorbed sulfapyridine and 5-aminosalicylic acid and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. The majority of 5-ASA stays within the colonic lumen and is excreted as 5-aminosalicylic acid and acetyl-5-aminosalicylic acid in the feces. The half-life of Denosumab is After Cmax, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25. 4 days (SD = 8. 5 days; n = 46). The half-life of Sulfasalazine is The observed plasma half-life for intravenous sulfasalazine is 7. 6 ± 3. 4 hours. In fast acetylators, the mean plasma half-life of sulfapyridine is 10. 4 hours while in slow acetylators, it is 14. 8 hours. Due to low plasma levels produced by. 5-aminosalicylic acid after oral administration, reliable estimates of plasma half-life are not possible. The clearance of Denosumab is No information is available on the clearance of denosumab. The clearance of Sulfasalazine is The calculated clearance of sulfasalazine following intravenous administration was 1 L/hr. Renal clearance was estimated to account for 37% of total clearance. Denosumab toxicity includes Denosumab is contraindicated for use in pregnant women because it may cause harm to a fetus. There are insufficient data with denosumab use in pregnant women to inform any drug-associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes,. abnormal bone growth, and decreased neonatal growth. In clinical trials, hypercalcemia has been reported in pediatric patients with osteogenesis imperfect treated with denosumab products, including Prolia. Some cases required hospitalization and were complicated by acute renal injury. Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years. The carcinogenic and genotoxic potential of denosumab has not been evaluated in long-term animal studies. Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg). Sulfasalazine toxicity includes Two-year oral carcinogenicity studies were conducted in male and female F344/N rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m2), 168 (991 mg/m2), and 337. 5 (1991 mg/m2) mg/kg/day doses in rats. A statistically significant increase in the incidence of urinary bladder transitional cell papillomas was observed in male rats. In female rats, two (4%) of the 337. 5 mg/kg rats had transitional cell papilloma of the kidney. The increased incidence of neoplasms in the urinary bladder and kidney of rats. was also associated with an increase in renal calculi formation and hyperplasia of transitional cell epithelium. For the mouse study, sulfasalazine was tested at 675 (2025 mg/m2), 1350 (4050 mg/m2), and 2700 (8100 mg/m2) mg/kg/day. The incidence of hepatocellular adenoma or carcinoma in male and female mice was significantly greater than the control at all doses tested. Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) and in L51784 mouse lymphoma cell assay at the HGPRT gene. However, sulfasalazine showed an equivocal mutagenic response in the micronucleus assay of mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid exchange, chromosomal aberration, and micronucleus assays in lymphocytes obtained from humans. Impairment of male fertility was observed in reproductive studies performed in rats at a dose of 800 mg/kg/day (4800 mg/m2). Oligospermia and infertility have been described in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects. There are no adequate and well-controlled studies of sulfasalazine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 6 times the human maintenance dose of 2 g/day based on body surface area and have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There have been case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy, but the role of sulfasalazine in these defects has not been established. However, oral sulfasalazine inhibits the absorption and metabolism of folic acid which may interfere with folic acid supplementation (see Drug Interactions) and diminish the effect of periconceptional folic acid supplementation that has been shown to decrease the risk of NTDs. A national survey evaluated the outcome of pregnancies associated with inflammatory bowel disease (IBD). In a group of 186 women treated with sulfasalazine alone or sulfasalazine and concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable to that for 245 untreated IBD pregnancies as well as to pregnancies in the general population. A study of 1,455 pregnancies associated with exposure to sulfonamides indicated that this group of drugs, including sulfasalazine, did not appear to be associated with fetal malformation. A review of the medical literature covering 1,155 pregnancies in women with ulcerative colitis suggested that the outcome was similar to that expected in the general population. No clinical studies have been performed to evaluate the effect of sulfasalazine on the growth development and functional maturation of children whose mothers received the drug during pregnancy. Brand names of Denosumab include Prolia, Xgeva. Brand names of Sulfasalazine include Azulfidine, Salazopyrin, Salazopyrin En-tabs. No synonyms are available for Denosumab. No synonyms are available for Sulfasalazine. Salazosulfapiridina Salazosulfapyridine Salazosulfapyridinum Salicylazosulfapyridine Sulfasalazin Sulfasalazina Sulfasalazine Sulfasalazinum Denosumab summary: It is Denosumab is a RANK ligand (RANKL) inhibitor used for the management of osteoporosis in patients at high risk for bone fractures. Sulfasalazine summary: It is Sulfasalazine is a salicylate used to treat Crohn's disease, ulcerative colitis, and rheumatoid arthritis. Answer: The coadministration of denosumab with immunosuppressive agents poses a high risk of serious infection than with denosumab alone.

Denosumab

Drug A is Rituximab. Drug B is Nadolol. The severity of the interaction is moderate. Nadolol may increase the hypotensive activities of Rituximab. When rituximab is administered intravenously as an infusion, hypotension was one of the most common adverse reactions associated with the use of the medication - typically as an infusion related reaction. As a consequence, if a patient using an antihypertensive agent(s) is also administered rituximab, there is a concern that the additive, combined blood pressure lowering effects of both kinds of medication could increase the risk of generating potentially severe hypotension in patients. Rituximab is indicated for Rituximab is indicated for the treatment of adult patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin’s Lymphoma (NHL) as a single agent. Also, it is indicated for the treatment of adult patients with previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy. Additionally, rituximab is indicated for the treatment of adult patients with non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; and previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens. Rituximab, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL). In combination with methotrexate, rituximab is indicated for the treatment of adult patients with moderately-to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. Additionally, rituximab, in combination with glucocorticoids, is indicated for the treatment of adult and pediatric patients 2 years of age and older with Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA). RITUXAN (rituximab injection for intravenous use) is indicated for the treatment of pediatric patients aged 6 months and older with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL) in combination with chemotherapy; as well as the treatment of adult patients with moderate to severe pemphigus vulgaris. These indications for RITUXAN are not included in the labels of rituximab biosimilar products (rituximab-arrx, rituximab-abbs, rituximab-pvvr). The combination product RITUXAN HYCELA (rituximab and hyaluronidase human injection, for subcutaneous use) is not indicated for the treatment of non-malignant conditions. Nadolol is indicated for Nadolol is indicated to treat angina pectoris and hypertension. Another product formulated with bendroflumethiazide is indicated to treat hypertension. Rituximab pharmacodynamics: Rituximab is a chimeric murine/human monoclonal antibody that binds to the CD20 antigen. CD20 is predominantly expressed on the surface of pre-B and mature B-lymphocytes, allowing rituximab to target and promote lysis in this specific type of cells. In Non-Hodgkin's Lymphoma patients, rituximab treatment depleted circulating and tissue-based B-cells. In a study that included 166 patients, CD19-positive B-cells were depleted within three weeks, and in 83% of patients, cell depletion lasted up to 6-9 months. B-cell levels started to recover at approximately 6 months and returned to normal 12 months after treatment was completed. Approximately 14% of Non-Hodgkin's Lymphoma patients had IgM or IgG serum levels below the normal range. Most rheumatoid arthritis (RA) patients treated with rituximab showed a near-complete depletion of peripheral B lymphocytes within 2 weeks after the first dose. Peripheral B-cell depletion was sustained for at least 6 months, and in approximately 4% of RA patients, peripheral B-cell depletion was sustained for more than 3 years after a single course of rituximab treatment. Total IgG, IgA, and, more specifically, IgM levels were lower 24 weeks after the first cycle of rituximab treatment (2. 8%, 0. 8% and 10% below the lower limit of normal, respectively). However, the clinical consequences of this decrease in immunoglobulin levels in RA patients are not clear at this time. Treatment with rituximab in patients with RA was also associated with a decreased level of inflammation markers. In patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) treated with rituximab, CD19 B-cells in peripheral blood were depleted to less than 10 cells/μl after the first two infusions. By month 6, approximately 84% of patients had the same level of peripheral blood CD19 B-cells, and by month 12, 81% of patients demonstrated signs of B-cell return with counts >10 cells/μL. By Month 18, the majority of patients (87%) had counts >10 cells/μL. Nadolol pharmacodynamics: Nadolol is a nonselective beta adrenal receptor blocker that is used to lower blood pressure. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as patients start at doses of 40mg daily but may be increased to doses as high as 240mg daily. Patients taking nadolol should not aburptly stop taking it as this may lead to exacerbation of ischemic heart disease. The mechanism of action of Rituximab is that it Rituximab is a monoclonal antibody that targets CD20, an antigen expressed on the surface of pre-B and mature B-lymphocytes. About 85% of non-Hodgkin’s lymphoma (NHL) cases are B-cell lymphomas, characterized by the high expression of CD19, CD20 and CD22 cell surface antigens. CD20 is involved in cell cycle regulation, apoptosis and calcium signaling. By targeting CD20, rituximab promotes cell lysis while sparing hematopoietic and plasma cells without this surface antigen. It has been suggested that cell lysis mechanisms triggered by rituximab include complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Rituximab is part of the immunoglobulin G1 (IgG1) subclass of antibodies, and is formed by a murine variable region (Fab region) and a human constant region (Fc region). The Fab region gives rituximab its specificity for CD20, while the Fc region interacts with cell surface receptors to activate the immune system, leading to the depletion of circulating B lymphocytes. In regards to the mechanism of action in rheumatoid arthritis (RA), B-cells are thought to play a role in the pathogenesis of RA and the associated condition of chronic synovitis. B-cells may act at various sites in the autoimmune/inflammatory process through the production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and the production of proinflammatory cytokines. The administration of rituximab in this condition has resulted in significant clinical and symptomatic improvements. Rituximab is also indicated for the treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), two conditions characterized by the presence of circulating antineutrophil cytoplasmic antibodies and increased B-cell activity. It has been suggested that rituximab depletes CD20 B-cells at a higher rate in GPA and MPA patients with high levels of Fc receptor-like 5 (FCRL5). The mechanism of action of Nadolol is that it Although nadolol is described as a non selective beta blocker, it does not interact with beta 3 adrenal receptors. Antagonism of beta-1 and beta-2 adrenoceptors in the heart inhibits cyclic AMP and its signalling pathway, decreasing the strength and speed of contractions as well as the speed of relaxation and conduction. Antagonism of beta-2 adrenoceptors in the smooth muscle cells of the vasculature inhibits their relaxation, leading to an increase in peripheral vascular resistance and reducing the risk of severe hypotension. The increase in peripheral vascular resistance may contribute to the decrease in insulin sensitivity associated with nadolol use. Antagonism of beta-1 adrenoceptors in the juxtaglomerular apparatus of the kidney inhibits the release of renin, and therefore angiotensin II mediated vasoconstriction, aldosterone mediated water retention, and the release of epinephrine. Antagonism of beta-2 adrenoceptors in the liver and skeletal muscle inhibits glycogenolysis, in the lungs prevents bronchodilation, and in the pancrease inhibits insulin release. Rituximab absorption: Rituximab follows a linear pharmacokinetic model. In patients with non-Hodgkin’s lymphoma (NHL) administered 4 doses of 375 mg/m of rituximab (IV) weekly, detectable levels were observed 3-6 months after treatment completion. The pharmacokinetic profile of rituximab administered in combination with 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy was similar to the one observed when administered alone. In patients with rheumatoid arthritis (RA) administered 2 doses of 500 mg of rituximab, the Cmax of the first and second infusions were 157 (SD ± 46) and 183 (SD ± 55) mcg/mL. In patients administered 2 doses of 1,000 mg of rituximab, the Cmax of the first and second infusions were 318 (SD ± 86) and 381 (SD ± 98) mcg/mL. In pediatric patients (6-17 years old) with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) given four doses of 375 mg/m of rituximab intravenously once a week, the AUC 0-180 was 9787 µg/mL⋅day (range from 4838 to 20446 µg/mL⋅day). In adult patients given the same dose, the AUC 0-180 of rituximab was 10302 µg/mL⋅day (range from 3653 to 21874 µg/mL⋅day). The bioavailability of rituximab administered intravenously is expected to be close to 100%. Compared to rituximab administered intravenously, the bioavailability of RITUXAN HYCELA, a combination product of rituximab and hyaluronidase (human recombinant), is 64. 6% in patients with follicular lymphoma and 63. 4% in patients with chronic lymphocytic leukemia (CLL). Nadolol absorption: Oral doses of nadolol are approximately 30% absorbed. In healthy subjects, nadolol has a Tmax of 2. 7h with a Cmax or 69±15ng/mL following a 60mg oral dose and 132±27ng/mL after a 120mg oral dose. The AUC following a 60mg oral dose was 1021ng*h/mL and following a 120mg oral dose was 1913±382ng*h/mL. The volume of distribution of Rituximab is Based on a pharmacokinetic analysis that included 2005 patients with rheumatoid arthritis (RA), the volume of distribution of rituximab is 3. 1 L. In pediatric patients (6-17 years old) with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) given four doses of 375 mg/m of rituximab intravenously once a week, the volume of distribution was 2. 28 L (range from 1. 43 to 3. 17 L). In adult patients given the same dose, the volume of distribution was 3. 12 L (range from 2. 42 to 3. 91 L). In patients with pemphigus vulgaris given an intravenous infusion of 1000 mg of rituximab on days 1, 15, 168, and 182, the volume of distribution was 3. 49 L (range from 2. 48 to 5. 22 L). The volume of distribution of Nadolol is In healthy subjects, the volume of distribution of nadolol is 147-157L. Rituximab is Not available. bound to plasma proteins. Nadolol is Nadolol is approximately 30% bound to plasma protein. Nadolol binds to alpha-1-acid glycoprotein in plasma. bound to plasma proteins. Rituximab metabolism: As a monoclonal antibody, rituximab is expected to be metabolized by proteases throughout the body. Nadolol metabolism: Nadolol is not metabolized by the liver in humans. Rituximab is eliminated via Monoclonal antibodies (mAb) such as rituximab trigger the formation of antidrug antibodies (ADAs) that form ADA-mAb immune complexes. The endogenous elimination of these immune complexes is mediated by the reticuloendothelial system, most likely via fragment crystallizable-gamma (Fcγ)-mediated endocytosis. Nadolol is eliminated via Nadolol is not metabolized in the liver and excreted mainly in the urine. In healthy subjects, following intravenous dosing, 60% of a dose is eliminated in the urine and 15% in the feces after 72 hours. The remainder of the dose is expected to be eliminated in the feces afterwards. The half-life of Rituximab is In patients with non-Hodgkin's lymphoma (NHL) treated with rituximab once a week or once every three weeks (n=298), the median terminal elimination half-life was 22 days (range of 6. 1-52 days). In patients with chronic lymphocytic leukemia (CLL) treated with rituximab (n=21), the estimated median terminal half-life was 32 days (range of 14-62 days). Based on a pharmacokinetic analysis that included 2005 patients with rheumatoid arthritis (RA), the mean terminal elimination half-life of rituximab is 18. 0 days. In pediatric patients (6-17 years old) with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) given four doses of 375 mg/m of rituximab intravenously once a week, the terminal half-life was 22 days (range from 11 to 42 days). In adult patients given the same dose, the terminal half-life was 25 days (range from 11 to 52 days). In patients with pemphigus vulgaris given an intravenous infusion of 1000 mg of rituximab, the terminal half-life was 21. 1 days (range from 9. 3 to 36. 2 days) in the first infusion cycle (days 1 and 15), and 26. 2 days (range from 16. 4 to 42. 8 days) in the second infusion cycle (days 168 and 182). The half-life of Nadolol is The half life of nadolol is 20 to 24 hours. The clearance of Rituximab is In patients with non-Hodgkin’s lymphoma (NHL), those with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had higher rituximab clearance. Based on a pharmacokinetic analysis that included 2005 patients with rheumatoid arthritis (RA), the clearance of rituximab is 0. 335 L/day. In pediatric patients (6-17 years old) with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) given four doses of 375 mg/m of rituximab intravenously once a week, clearance was 0. 222 L/day (range from 0. 0996 to 0. 381 L/day). In adult patients given the same dose, clearance was 0. 279 L/day (range from 0. 113 to 0. 653 L/day). In patients with pemphigus vulgaris given an intravenous infusion of 1000 mg of rituximab, clearance was 0. 30 L/day (range from 0. 16 to 1. 51 L/day) in the first infusion cycle (days 1 and 15), and 0. 24 L/day (range from 0. 13 to 0. 45 L/day) in the second infusion cycle (days 168 and 182). The clearance of Nadolol is In healthy subjects, the total body clearance of nadolol is 219-250mL/min and the renal clearance is 131-150mL/min. Rituximab toxicity includes Toxicity information regarding rituximab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as fatal infusion-related reactions and severe mucocutaneous reactions. Symptomatic and supportive measures are recommended. No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of rituximab or to determine potential effects on fertility in males or females. The maximum tolerated dose of rituximab in mice administered intraperitoneally is higher than 100 mg/kg. Nadolol toxicity includes The oral LD 50 in mice is 4500mg/kg. Patients experiencing an overdose may present with bradycardia, cardiac failure, hypotension, and bronchospasm. An overdose may be treated with atropine for bradycardia, digitalis and diuretics for cardiac failure, vasopressors for hypotension, and beta-2 stimulants for bronchospasms, as well as gastric lavage and hemodialysis. Brand names of Rituximab include MabThera, Riabni, Rituxan, Rituxan Hycela, Ruxience, Truxima. Brand names of Nadolol include Corgard. No synonyms are available for Rituximab. No synonyms are available for Nadolol. Rituximab summary: It is Rituximab is a monoclonal anti-CD20 antibody used to treat non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Wegener's granulomatosis, pemphigus vulgaris, and rheumatoid arthritis. Nadolol summary: It is Nadolol is a non-selective beta-adrenergic antagonist used for the management of arrhythmias, angina pectoris, and hypertension. Answer: When rituximab is administered intravenously as an infusion, hypotension was one of the most common adverse reactions associated with the use of the medication - typically as an infusion related reaction. As a consequence, if a patient using an antihypertensive agent(s) is also administered rituximab, there is a concern that the additive, combined blood pressure lowering effects of both kinds of medication could increase the risk of generating potentially severe hypotension in patients.

Rituximab

Drug A is Acetazolamide. Drug B is Valproic acid. The severity of the interaction is moderate. The risk or severity of CNS depression can be increased when Valproic acid is combined with Acetazolamide. Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. Acetazolamide is indicated for adjunctive treatment of: edema due to congestive heart failure; drug-induced edema; centrencephalic epilepsies; chronic simple (open-angle) glaucoma. Valproic acid is indicated for Indicated for: 1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures. 2) Adjunctive therapy in the management of multiple seizure types that include absence seizures. 3) Prophylaxis of migraine headaches. 4) Acute management of mania associated with bipolar disorder. Off-label uses include: 1) Maintenance therapy for bipolar disorder. 2) Treatment for acute bipolar depression. 3) Emergency treatment of status epilepticus. Acetazolamide pharmacodynamics: Acetazolamide is a potent carbonic anhydrase inhibitor, effective in the control of fluid secretion, in the treatment of certain convulsive disorders and in the promotion of diuresis in instances of abnormal fluid retention. Acetazolamide is not a mercurial diuretic. Rather, it is a nonbacteriostatic sulfonamide possessing a chemical structure and pharmacological activity distinctly different from the bacteriostatic sulfonamides. Valproic acid pharmacodynamics: Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches. It also improves symptom control in bipolar mania. Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder. Valproate is hepatotoxic and teratogenic. The reasons for this are unclear but have been attributed to the genomic effects of the drug. A small proof-of concept study found that valproate increases clearance of human immunodeficiency virus (HIV) when combined with highly active antiretroviral therapy (HAART) by reactivating the virus to allow clearance, however, a larger multicentre trial failed to show a significant effect on HIV reservoirs when added to HAART. The FDA labeling contains a warning regarding HIV reactivation during valproate use. The mechanism of action of Acetazolamide is that it The anticonvulsant activity of Acetazolamide may depend on a direct inhibition of carbonic anhydrase in the CNS, which decreases carbon dioxide tension in the pulmonary alveoli, thus increasing arterial oxygen tension. The diuretic effect depends on the inhibition of carbonic anhydrase, causing a reduction in the availability of hydrogen ions for active transport in the renal tubule lumen. This leads to alkaline urine and an increase in the excretion of bicarbonate, sodium, potassium, and water. The mechanism of action of Valproic acid is that it The exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action. Valproate is known to inhibit succinic semialdehyde dehydrogenase. This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity. A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA. It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK). These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABA A receptors which contribute further to increased GABAergic activity. Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase. This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect. Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium. The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis. Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton. Valproate also appears to impact fatty acid metabolism. Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action. Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase. Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production. Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor. Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated. The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients. Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong. H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective effects. No absorption information is available for Acetazolamide. Valproic acid absorption: The intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state. The oral delayed-release tablet formulation has a Tmax of 4 hours. Differences in absorption rate are expected from other formulations but are not considered to be clinically important in the context of chronic therapy beyond impacting frequency of dosing. Differences in absorption may create earlier Tmax or higher Cmax values on initiation of therapy and may be affected differently by meals. The extended release tablet formulation had Tmax increase from 4 hours to 8 hours when taken with food. In comparison, the sprinkle capsule formulation had Tmax increase from 3. 3 hours to 4. 8 hours. Bioavailability is reported to be approximately 90% with all oral formulations with enteric-coated forms possibly reaching 100%. No volume of distribution information is available for Acetazolamide. The volume of distribution of Valproic acid is 11 L/1. 73m. Acetazolamide is 98% bound to plasma proteins. Valproic acid is Protein binding is linear at low concentrations with a free fraction of approximately 10% at 40 mcg/mL but becomes non-linear at higher concentrations with a free fraction of 18. 5% at 135 mcg/mL. This may be due to binding at separate high and low-affinity sites on albumin proteins. Binding is expected to decrease in the elderly and patients with hepatic dysfunction. bound to plasma proteins. No metabolism information is available for Acetazolamide. Valproic acid metabolism: Most drug is metabolized to glucuronide conjugates (30-50%) of the parent drug or of metabolites. Another large portion is metabolized through mitochondrial β-oxidation (40%). The remainder of metabolism (15-20%) occurs through oxidation, hydroxylation, and dehydrogenation at the ω, ω 1, and ω 2 positions resulting in the formation of hydroxyls, ketones, carboxyls, a lactone metabolite, double bonds, and combinations. Acetazolamide is eliminated via No route of elimination available. Valproic acid is eliminated via Most drug is eliminated through hepatic metabolism, about 30-50%. The other major contributing pathway is mitochondrial β-oxidation, about 40%. Other oxidative pathways make up an additional 15-20%. Less than 3% is excreted unchanged in the urine. The half-life of Acetazolamide is 3 to 9 hours. The half-life of Valproic acid is 13-19 hours. The half-life in neonates ranges from 10-67 hours while the half-life in pediatric patients under 2 months of age ranges from 7-13 hours. No clearance information is available for Acetazolamide. The clearance of Valproic acid is 0. 56 L/hr/m Pediatric patients between 3 months and 10 years of age have 50% higher clearances by weight. Pediatric patients 10 years of age or older approximate adult values. No toxicity information is available for Acetazolamide. Valproic acid toxicity includes LD 50 Values Oral, mouse: 1098 mg/kg Oral, rat: 670 mg/kg Overdose Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. The unbound fraction may be removed by hemodialysis. Naloxone has been demonstrated to reverse the CNS depressant effects of overdose but may also reverse the anti-epileptic effects. Reproductive Toxicity Valproate use in pregnancy is known to increase the risk of neural tube defects and other structural abnormalities. The risk of spina bifida increases from 0. 06-0. 07% in the normal population to 1-2% in valproate users. The North American Antiepileptic Drug (NAAED). Pregnancy Registry reports a major malformation rate of 9-11%, 5 times the baseline rate. These malformations include neural tube defects, cardiovascular malformations, craniofacial defects (e. g., oral clefts, craniosynostosis), hypospadias, limb malformations (e. g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems. Other antiepileptic drugs, lamotrigine, carbemazepine, and phenytoin, have been found to reduce IQ in children exposed in utero. Valproate was also studied however the results did not achieve statistical significance (97 IQ (CI is 94-101)). Observational studies report an absolute risk increase of 2. 9% (relative risk 2. 9 times baseline) of autism spectrum disorder in children exposed to valproate in utero. There have been case reports of fatal hepatic failure in children of mothers who used valproate during pregnancy. There have been reports of male infertility when taking valproate. Lactation Valproate is excreted in human milk. Data in the published literature describe the presence of valproate in human milk (range: 0. 4 mcg/mL to 3. 9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0. 7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate. via breast milk. Other Toxicity Considerations Use in pediatrics under 2 years of age increases the risk of fatal hepatotoxicity. Brand names of Acetazolamide include No brand names available. Brand names of Valproic acid include Depakene, Depakote, Epival. No synonyms are available for Acetazolamide. Acetazolamida Acétazolamide Acetazolamide Acetazolamidum No synonyms are available for Valproic acid. ácido valproico acidum valproicum Dipropylacetic acid Valproate Valproic acid Valproinsäure Acetazolamide summary: It is Acetazolamide is a carbonic anhydrase inhibitor used to treat edema from heart failure or medications, certain types of epilepsy, and glaucoma. Valproic acid summary: It is Valproic acid is an anticonvulsant used to control complex partial seizures and both simple and complex absence seizures. Answer: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

Acetazolamide

Drug A is Octreotide. Drug B is Esomeprazole. The severity of the interaction is moderate. Esomeprazole can cause a decrease in the absorption of Octreotide resulting in a reduced serum concentration and potentially a decrease in efficacy. Drugs that alter gastrointestinal pH, such as H2 blockers, antacids, or proton pump inhibitors may interfere with the absorption and bioavailability of oral octreotide. Octreotide is indicated for Octreotide by injection is used for the treatment of acromegaly and the reduction of flushing and diarrhea symptoms related to carcinoid tumors and/or vasoactive intestinal peptide (VIPoma) tumors. The delayed-release oral formulation is used for the long-term treatment of acromegaly in patients who tolerate and respond adequately to injectable octreotide and lanreotide. Esomeprazole is indicated for Esomeprazole is indicated for the treatment of acid-reflux disorders including healing and maintenance of erosive esophagitis, and symptomatic gastroesophageal reflux disease (GERD), peptic ulcer disease, H. pylori eradication, prevention of gastrointestinal bleeds with NSAID use, and for the long-term treatment of pathological hypersecretory conditions including Zollinger-Ellison Syndrome. Octreotide pharmacodynamics: Octreotide mimics the naturally occurring hormone known as somatostatin. Like somatostatin, it demonstrates activity against growth hormone and glucagon, treating the disordered tissue growth and insulin regulation in patients with acromegaly. In addition, octreotide relieves the flushing and diarrhea associated with gastrointestinal tumors by reducing splanchnic blood flow and various gastrointestinal hormones associated with diarrhea. Product labeling warns that octreotide may reduce gallbladder contractility, bile secretion, and the release of thyroid-stimulating hormone (TSH) in healthy volunteers. In addition, reports of decreased vitamin B12 in patients treated with octreotide have been made. Ensure to monitor vitamin B12 levels in patients taking octreotide. Esomeprazole pharmacodynamics: Esomeprazole is a compound that inhibits gastric acid secretion and is indicated in the treatment of gastroesophageal reflux disease (GERD), the healing of erosive esophagitis, and H. pylori eradication to reduce the risk of duodenal ulcer recurrence. Esomeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic properties, but that suppress gastric acid secretion by specific inhibition of the H /K ATPase at the secretory surface of the gastric parietal cell. By doing so, it inhibits acid secretion into the gsatric lumen. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Esomeprazole is the s-isomer of Omeprazole, which is a racemate of the S- and R-enantiomer. Esomeprazole has been shown to inhibit acid secretion to a similar extent as Omeprazole, without any significant differences between the two compounds in vitro. PPIs such as esomeprazole have also been shown to inhibit the activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme necessary for cardiovascular health. DDAH inhibition causes a consequent accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginie (ADMA), which is thought to cause the association of PPIs with increased risk of cardiovascular events in patients with unstable coronary syndromes. Due to their good safety profile and as several PPIs are available over the counter without a prescription, their current use in North America is widespread. Long term use of PPIs such as esomeprazole has been associated with possible adverse effects, however, including increased susceptibility to bacterial infections (including gastrointestinal C. difficile ), reduced absorption of micronutrients including iron and B12, and an increased risk of developing hypomagnesemia and hypocalcemia which may contribute to osteoporosis and bone fractures later in life. The mechanism of action of Octreotide is that it Octreotide binds to somatostatin receptors coupled to phospholipase C through G proteins and leads to smooth muscle contraction in the blood vessels. Downstream effects that stimulate phospholipase C, the production of 1, 4,5-inositol triphosphate, and action on the L-type calcium channels lead to the inhibition of growth hormone, treating the various growth-hormone and metabolic effects of acromegaly. Octreotide's suppression of luteinizing hormone (LH), reduction in splanchnic blood flow, and inhibition of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide provide relief for the gastrointestinal and flushing symptoms of carcinoid and/or VIPoma tumors. The mechanism of action of Esomeprazole is that it Esomeprazole exerts its stomach acid-suppressing effects by preventing the final step in gastric acid production by covalently binding to sulfhydryl groups of cysteines found on the (H+, K+)-ATPase enzyme at the secretory surface of gastric parietal cells. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. As the binding of esomeprazole to the (H+, K+)-ATPase enzyme is irreversible and new enzyme needs to be expressed in order to resume acid secretion, esomeprazole's duration of antisecretory effect that persists longer than 24 hours. Octreotide absorption: After a subcutaneous dose, octreotide is absorbed completely upon administration. After the administration of an oral delayed-release capsule, peak concentrations were found to be 33% lower than after subcutaneous administration. The Cmax was attained at 1. 67–2. 5 hours after oral administration versus 30 minutes for the subcutaneous route. At 20 mg twice a day in patients with acromegaly, peak concentration was 2. 5 mg/nL versus 5. 30 ng/mL at 40 mg twice a day. AUC increases in proportion with the dose, regardless of the route. Esomeprazole absorption: After oral administration, peak plasma levels (Cmax) occur at approximately 1. 5 hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4. 32 μmol hr/L on Day 1 to 11. 2 μmol hr/L on Day 5 after 40 mg once daily dosing. The AUC after administration of a single 40 mg dose of Esomeprazole is decreased by 43% to 53% after food intake compared to fasting conditions. Esomeprazole should be taken at least one hour before meals. Combination Therapy with Antimicrobials: Esomeprazole magnesium 40 mg once daily was given in combination with Clarithromycin 500 mg twice daily and Amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady state AUC and Cmax of esomeprazole increased by 70% and 18%, respectively during triple combination therapy compared to treatment with esomeprazole alone. The observed increase in esomeprazole exposure during co-administration with clarithromycin and amoxicillin is not expected to produce significant safety concerns. The volume of distribution of Octreotide is In a pharmacokinetic study, the volume of distribution was 13. 6 L in healthy volunteers. One pharmacokinetic study revealed a volume of distribution ranging from 18. 1-30. 4L after intravenous administration in healthy volunteers. The volume of distribution of Esomeprazole is The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L. Octreotide is Approximately 65% of the dose is bound in the plasma to lipoproteins and albumin. bound to plasma proteins. Esomeprazole is Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 µmol/L. bound to plasma proteins. Octreotide metabolism: Octreotide has been reported to be heavily metabolized in the liver. Esomeprazole metabolism: Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole lack antisecretory activity. The major part of esomeprazole’s metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite. CYP2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole, since some 3% of Caucasians and 15 to 20% of Asians lack CYP2C19 and are termed Poor Metabolizers. However, the influence of CYP 2C19 polymorphism is less pronounced for esomeprazole than for omeprazole. At steady state, the ratio of AUC in Poor Metabolizers to AUC in the rest of the population (Extensive Metabolizers) is approximately 2. Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the liver, resulting in higher plasma levels of the S- than of the R-isomer. Nine major urinary metabolites have been detected. The two main metabolites have been identified as hydroxyesomeprazole and the corresponding carboxylic acid. Three major metabolites have been identified in plasma: the 5-O-desmethyl- and sulphone derivatives and hydroxyesomeprazole. The major metabolites of esomeprazole have no effect on gastric acid secretion. Octreotide is eliminated via About 32% of an oral octreotide dose is excreted into the urine and 30-40% is excreted by the liver into the feces. About 11% of the unchanged parent drug is found in the urine, and 2% of the unchanged parent drug can be recovered in the feces. Esomeprazole is eliminated via The plasma elimination half-life of esomeprazole is approximately 1 to 1. 5 hours. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces. The half-life of Octreotide is After a subcutaneous dose, the plasma half-life is estimated to be 0. 2 hours. The average elimination half-lives for subcutaneous and oral administration ranged from 2. 3 - 2. 7 hours and did not differ significantly. One pharmacokinetic study revealed a plasma half-life ranging from 72-113 minutes. The half-life of Esomeprazole is 1-1. 5 hours. The clearance of Octreotide is The total body clearance of octreotide is 7-10 L/h. One pharmacokinetic study revealed a total body clearance of 11. 4 L/h. No clearance information is available for Esomeprazole. Octreotide toxicity includes There is limited information regarding cases of octreotide overdose aside from case reports of an overdose with injectable octreotide. The dose ranged from 2. 4 mg/day to 6 mg/day administered by continuous infusion or subcutaneous administration of 1. 5 mg three times daily. Effects of an overdose with octreotide may include hypotension, brain hypoxia, arrhythmia, cardiac arrest, lactic acidosis, pancreatitis, hepatomegaly, diarrhea, flushing, lethargy, and weakness. Esomeprazole toxicity includes Blurred vision, confusion, drowsiness, dry mouth, flushing headache, nausea, rapid heartbeat, sweating. Brand names of Octreotide include Bynfezia, Mycapssa, Sandostatin. Brand names of Esomeprazole include Nexium, Vimovo. No synonyms are available for Octreotide. No synonyms are available for Esomeprazole. Esomeprazol Ésoméprazole Esomeprazole Esomeprazolum Perprazole Octreotide summary: It is Octreotide is a peptide drug used to treat acromegaly as well as diarrhea associated with metastatic carcinoid tumors and vasoactive intestinal peptide secreting tumors. Esomeprazole summary: It is Esomeprazole is a proton pump inhibitor used to treat GERD, reduce the risk of NSAID associated gastric ulcers, eradicate H. pylori, and to treat conditions causing gastric acid hypersecretion. Answer: Drugs that alter gastrointestinal pH, such as H2 blockers, antacids, or proton pump inhibitors may interfere with the absorption and bioavailability of oral octreotide.

Octreotide

Drug A is Octreotide. Drug B is Sotagliflozin. The severity of the interaction is moderate. The therapeutic efficacy of Sotagliflozin can be decreased when used in combination with Octreotide. Octreotide inhibits the secretion of glucagon and insulin, affecting blood glucose levels. [A214097] Drugs that lower blood glucose may be affected by concurrent administration of octreotide. Octreotide is indicated for Octreotide by injection is used for the treatment of acromegaly and the reduction of flushing and diarrhea symptoms related to carcinoid tumors and/or vasoactive intestinal peptide (VIPoma) tumors. The delayed-release oral formulation is used for the long-term treatment of acromegaly in patients who tolerate and respond adequately to injectable octreotide and lanreotide. Sotagliflozin is indicated for In the US, sotagliflozin is indicated to reduce the risk of cardiovascular death and heart failure in adults with heart failure, type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors. Octreotide pharmacodynamics: Octreotide mimics the naturally occurring hormone known as somatostatin. Like somatostatin, it demonstrates activity against growth hormone and glucagon, treating the disordered tissue growth and insulin regulation in patients with acromegaly. In addition, octreotide relieves the flushing and diarrhea associated with gastrointestinal tumors by reducing splanchnic blood flow and various gastrointestinal hormones associated with diarrhea. Product labeling warns that octreotide may reduce gallbladder contractility, bile secretion, and the release of thyroid-stimulating hormone (TSH) in healthy volunteers. In addition, reports of decreased vitamin B12 in patients treated with octreotide have been made. Ensure to monitor vitamin B12 levels in patients taking octreotide. Sotagliflozin pharmacodynamics: Sotagliflozin exerts its pharmacologic effects by slowing glucose absorption in the gastrointestinal tract and increasing the excretion of glucose in the urine. It is administered by mouth once daily before the first meal of the day. The use of SGLT2 inhibitors, including sotagliflozin, can cause diabetic ketoacidosis (DKA). Patients, especially those with a higher baseline risk of DKA, should be instructed on how and when to monitor for ketoacidosis and what actions to take when DKA is suspected. SGLT2 inhibitors, including sotagliflozin, also increase the risk of genital infections. This is due to the increase in urinary glucose excretion, which provides a relatively glucose-rich environment in which infectious agents may establish themselves. The mechanism of action of Octreotide is that it Octreotide binds to somatostatin receptors coupled to phospholipase C through G proteins and leads to smooth muscle contraction in the blood vessels. Downstream effects that stimulate phospholipase C, the production of 1, 4,5-inositol triphosphate, and action on the L-type calcium channels lead to the inhibition of growth hormone, treating the various growth-hormone and metabolic effects of acromegaly. Octreotide's suppression of luteinizing hormone (LH), reduction in splanchnic blood flow, and inhibition of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide provide relief for the gastrointestinal and flushing symptoms of carcinoid and/or VIPoma tumors. The mechanism of action of Sotagliflozin is that it Sodium-glucose co-transporter types 1 and 2 (SGLT1 and SGLT2) are integral in the transport of glucose in the body. SGLT1 is the major transporter for glucose absorption in the gastrointestinal tract, while SGLT2 is the predominant transporter responsible for reabsorption of glucose in the glomerulus. Sotagliflozin is a dual inhibitor of both SGLT1 and SGLT2. Inhibition of SGLT1 results in a delay in glucose absorption and a blunting of postprandial hyperglycemia, while inhibition of SGLT2 reduces renal reabsorption of filtered glucose, thereby increasing urinary glucose excretion. Octreotide absorption: After a subcutaneous dose, octreotide is absorbed completely upon administration. After the administration of an oral delayed-release capsule, peak concentrations were found to be 33% lower than after subcutaneous administration. The Cmax was attained at 1. 67–2. 5 hours after oral administration versus 30 minutes for the subcutaneous route. At 20 mg twice a day in patients with acromegaly, peak concentration was 2. 5 mg/nL versus 5. 30 ng/mL at 40 mg twice a day. AUC increases in proportion with the dose, regardless of the route. Sotagliflozin absorption: Following a single dose, the Tmax of sotagliflozin ranged from 1. 25 to 3 hours. Following multiple doses, the Tmax ranged from 2. 5 to 4 hours. The estimated oral bioavailability of sotagliflozin is 71%. The volume of distribution of Octreotide is In a pharmacokinetic study, the volume of distribution was 13. 6 L in healthy volunteers. One pharmacokinetic study revealed a volume of distribution ranging from 18. 1-30. 4L after intravenous administration in healthy volunteers. The volume of distribution of Sotagliflozin is Sotagliflozin has a mean apparent volume of distribution of 9392 L. Octreotide is Approximately 65% of the dose is bound in the plasma to lipoproteins and albumin. bound to plasma proteins. Sotagliflozin is Both sotagliflozin and its major metabolite, M19, are extensively (~98%) protein-bound in plasma, although the specific protein(s) to which they bind have not been elucidated. bound to plasma proteins. Octreotide metabolism: Octreotide has been reported to be heavily metabolized in the liver. Sotagliflozin metabolism: The major metabolite of sotagliflozin is a 3-O-glucuronide (M19), which comprised ~94% of the radioactivity in plasma following the oral administration of a radiolabeled dose of sotagliflozin. The M19 metabolite is effectively inactive, with >275-fold less activity at SGLT1 and SGLT2 compared to the parent drug. The primary route of metabolism is via glucuronidation by UGT1A9 (and both UGT1A1 and UGT2B7, to a lesser extent) as well as oxidation via CYP3A4. Octreotide is eliminated via About 32% of an oral octreotide dose is excreted into the urine and 30-40% is excreted by the liver into the feces. About 11% of the unchanged parent drug is found in the urine, and 2% of the unchanged parent drug can be recovered in the feces. Sotagliflozin is eliminated via Sotagliflozin is primarily eliminated via the renal route, with 57% of administered drug material appearing in the urine and 37% appearing in the feces. The half-life of Octreotide is After a subcutaneous dose, the plasma half-life is estimated to be 0. 2 hours. The average elimination half-lives for subcutaneous and oral administration ranged from 2. 3 - 2. 7 hours and did not differ significantly. One pharmacokinetic study revealed a plasma half-life ranging from 72-113 minutes. The half-life of Sotagliflozin is The mean terminal half-life of sotagliflozin ranged from 21 to 35 hours and from 19 to 26 hours for its M19 metabolite. The clearance of Octreotide is The total body clearance of octreotide is 7-10 L/h. One pharmacokinetic study revealed a total body clearance of 11. 4 L/h. The clearance of Sotagliflozin is In healthy volunteers, the mean apparent clearance of sotagliflozin ranged from 261 to 374 L/h. The mean apparent clearance estimated in a population of mostly type 1 diabetic patients was 239 L/h. Octreotide toxicity includes There is limited information regarding cases of octreotide overdose aside from case reports of an overdose with injectable octreotide. The dose ranged from 2. 4 mg/day to 6 mg/day administered by continuous infusion or subcutaneous administration of 1. 5 mg three times daily. Effects of an overdose with octreotide may include hypotension, brain hypoxia, arrhythmia, cardiac arrest, lactic acidosis, pancreatitis, hepatomegaly, diarrhea, flushing, lethargy, and weakness. Sotagliflozin toxicity includes Multiple doses of 800mg once daily (double the maximum recommended dose) have been administered to healthy volunteers without evidence of overdose symptoms. In the event of a suspected overdose, administer supportive treatment as clinically indicated. Brand names of Octreotide include Bynfezia, Mycapssa, Sandostatin. Brand names of Sotagliflozin include Inpefa. No synonyms are available for Octreotide. No synonyms are available for Sotagliflozin. Octreotide summary: It is Octreotide is a peptide drug used to treat acromegaly as well as diarrhea associated with metastatic carcinoid tumors and vasoactive intestinal peptide secreting tumors. Sotagliflozin summary: It is Sotagliflozin is an orally administered dual SGLT1/2 inhibitor used alongside insulin to improve glycemic control in patients with type 1 diabetes mellitus. Answer: Octreotide inhibits the secretion of glucagon and insulin, affecting blood glucose levels. [A214097] Drugs that lower blood glucose may be affected by concurrent administration of octreotide.

Octreotide

Drug A is Bumetanide. Drug B is Nalbuphine. The severity of the interaction is moderate. The therapeutic efficacy of Bumetanide can be decreased when used in combination with Nalbuphine. Opioids can induce the release of antidiuretic hormone, reducing the therapeutic efficacy of different diuretics. The release of antidiuretic hormone is thought to be related to kappa receptor binding. Bumetanide is indicated for the treatment of edema associated with congestive heart failure, hepatic and renal disease including the nephrotic syndrome. Nalbuphine is indicated for the relief of moderate to severe pain. Bumetanide pharmacodynamics: Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in patients in whom high doses of furosemide are ineffective. There is however no reason not to use bumetanide as a first choice drug. The main difference between the two substances is in bioavailability. Bumetanide has more predictable pharmacokinetic properties as well as clinical effect. In patients with normal renal function, bumetanide is 40 times more effective than furosemide. Nalbuphine pharmacodynamics: Nalbuphine is a synthetic opioid agonist-antagonist analgesic of the phenanthrene series. Nalbuphine's analgesic potency is essentially equivalent to that of morphine on a milligram basis. The opoioid antagonist activity of nalbuphine is about one-fourth to that of nalorphine and 10 times to that of pentazocine. Nalbuphine by itself has potent opioid antagonist activity at doses equal to or lower than its analgesic dose. When administered following or concurrent with mu agonist opioid analgesics (e. g., morphine, oxymorphone, fentanyl), nalbuphine may partially reverse or block opioid-induced respiratory depression from the mu agonist analgesic. Nalbuphine may precipitate withdrawal in patients dependent on opioid drugs. Nalbuphine should be used with caution in patients who have been receiving mu opioid analgesics on a regular basis. The mechanism of action of Bumetanide is that it Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. The mechanism of action of Nalbuphine is that it The exact mechanism of action is unknown, but is believed to interact with an opiate receptor site in the CNS (probably in or associated with the limbic system). The opiate antagonistic effect may result from competitive inhibition at the opiate receptor, but may also be a result of other mechanisms. Nalbuphine is thought primarily to be a kappa agonist. It is also a partial mu antagonist analgesic, with some binding to the delta receptor and minimal agonist activity at the sigma receptor. Bumetanide absorption: Bumetanide is completely absorbed (80%), and the absorption is not altered when taken with food. Bioavailability is almost complete. Nalbuphine absorption: The mean absolute bioavailability was 81% and 83% for the 10 and 20 mg intramuscular doses, respectively, and 79% and 76% following 10 and 20 mg of subcutaneous nalbuphine. Clinical studies show that the duration of analgesic activity of the drug can range from 3 to 6 hours. No volume of distribution information is available for Bumetanide. No volume of distribution information is available for Nalbuphine. Bumetanide is 97% bound to plasma proteins. Nalbuphine is Not appreciably bound. bound to plasma proteins. Bumetanide metabolism: 45% is secreted unchanged. Urinary and biliary metabolites are formed by oxidation of the N-butyl side chain. No metabolism information is available for Nalbuphine. Bumetanide is eliminated via Oral administration of carbon-14 labeled Bumex to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Biliary excretion of Bumex amounted to only 2% of the administered dose. Nalbuphine is eliminated via No route of elimination available. The half-life of Bumetanide is 60-90 minutes. The half-life of Nalbuphine is The plasma half-life of nalbuphine is about 5 hours. The clearance of Bumetanide is 0. 2 - 1. 1 mL/min/kg [preterm and full-term neonates with respiratory disorders]. 2. 17 mL/min/kg [neonates receiving bumetanide for volume overload] 1. 8 +/- 0. 3 mL/min/kg [geriatric subjects] 2. 9 +/- 0. 2 mL/min/kg [younger subjects] No clearance information is available for Nalbuphine. Bumetanide toxicity includes Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels. Nalbuphine toxicity includes Oral, acute LD50 is 1100 mg/kg in dog. Symptoms of overdose include primarily sleepiness and mild dysphoria. Brand names of Bumetanide include Bumex, Burinex. Brand names of Nalbuphine include No brand names available. No synonyms are available for Bumetanide. Bumetanide Bumetanidum No synonyms are available for Nalbuphine. Nalbuphin Nalbuphine Nalbuphinum Bumetanide summary: It is Bumetanide is a sulfamyl diuretic used to treat edema in congestive heart failure, hepatic and renal disease, and nephrotic syndrome. Nalbuphine summary: It is Nalbuphine is an opioid agonist-antagonist used to treat pain, for pre and postoperative analgesia, and for analgesia in labor and delivery. Answer: Opioids can induce the release of antidiuretic hormone, reducing the therapeutic efficacy of different diuretics. The release of antidiuretic hormone is thought to be related to kappa receptor binding.

Bumetanide

Drug A is Belantamab mafodotin. Drug B is Loperamide. The severity of the interaction is moderate. The serum concentration of Belantamab mafodotin can be increased when it is combined with Loperamide. The concomitant administration of two or more substrates of the p-gp transporter may result in the increased serum concentration of at least one or more of the substrates, due to competition among the substrates for the p-gp transporter. Depending on the p-gp substrate, this may result in drug toxicity and serious conditions such as excessive bleeding, cardiac conduction defects or organ toxicity, among many other effects. Belantamab mafodotin is indicated for Belantamab mafodotin is indicated in the treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Loperamide is indicated for Loperamide is indicated for the relief of diarrhea, including Travelers’ Diarrhea. As an off-label use, it is often used to manage chemotherapy-related diarrhea. Belantamab mafodotin pharmacodynamics: Belantamab mafodotin treats multiple myeloma through antibody dependant cell mediated cytotoxicity as well as G2/M cell cycle arrest. It has a narrow therapeutic index due to the incidence of adverse effects, and a long duration of action as it is given every 3 weeks. Patients should be counselled regarding the risk of keratopathy. Loperamide pharmacodynamics: Loperamide is an anti-diarrheal agent that provides symptomatic relief of diarrhea. It decreases peristalsis and fluid secretion in the gastrointestinal tract, delays colonic transit time, and increases the absorption of fluids and electrolytes from the gastrointestinal tract. Loperamide also increases rectal tone, reduces daily fecal volume, and increases the viscosity and bulk density of feces. It also increases the tone of the anal sphincter, thereby reducing incontinence and urgency. The onset of action is about one hour and the duration of action can be up to three days. While loperamide is a potent mu-opioid receptor agonist, it does not mediate significant analgesic activity at therapeutic and supratherapeutic doses. However, at high doses of loperamide, inhibition of P-glycoprotein-mediated drug efflux may allow loperamide to cross the blood-brain barrier, where loperamide can exert central opioid effects and toxicity. At very high plasma concentrations, loperamide can interfere with cardiac conduction. Because loperamide inhibits the Na -gated cardiac channels and ether-a-go-go–related gene potassium channels, the drug can prolong the QRS complex and the QTc interval, which can lead to ventricular dysrhythmias, monomorphic and polymorphic ventricular tachycardia, torsade de pointes, ventricular fibrillation, Brugada syndrome, cardiac arrest, and death. The mechanism of action of Belantamab mafodotin is that it Belantamab mafodotin, or GSK2857916, is an afucosylated monoclonal antibody that targets B cell maturation antigen (BCMA) conjugated to the microtubule distrupter monomethyl auristatin-F (MMAF). Afucosylation of the Fc region of monoclonal antibodies enhances binding to the Fc region, which enhances antibody dependant cell mediated cytoxicity. BCMA is uniquely expressed on CD138-positive myeloma cells. Targeting BCMA allows belantamab mafodotin to be highly selective in its delivery of MMAF to multiple myeloma cells. Belantamab mafodotin binds to BCMA, is internalised into cells, and releases MMAF. The MMAF payload binds to tubulin, stopping the cell cycle at the DNA damage checkpoint between the G2 and M phases, resulting in apoptosis. The mechanism of action of Loperamide is that it Enteric neurons synthesize and release endogenous opioid peptides and other neurotransmitters, such as acetylcholine and substance P. Endogenous opioids bind to opioid receptors expressed on these neurons to regulate gastrointestinal signalling, motility, and balance of fluids and electrolytes. Loperamide acts on the mu-opioid receptor expressed on the circular and longitudinal intestinal muscle. Receptor binding leads to the recruitment of G-protein receptor kinases and the activation of downstream molecular cascades that inhibit enteric nerve activity. By inhibiting the excitability of enteric neurons, loperamide suppresses neurotransmitter release, pre-synaptic and post-synaptic inhibition of transmission of excitatory and inhibitory motor pathways, and secretomotor pathways. Loperamide inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis and increasing intestinal transit time. Loperamide stimulates the intestinal absorption of water and electrolytes by inhibiting calmodulin. Loperamide can bind to and hyperpolarize submucosal secretomotor neurons, promoting dry, hard stools. Belantamab mafodotin absorption: Belantamab mafodotin at a dose of 2. 5mg/kg reaches a Cmax of 42 µg/mL, with a Tmax of 0. 78 hours, and an AUC of 4666 µg*h/mL. Loperamide absorption: Loperamide is well absorbed from the gastrointestinal tract; however, it undergoes extensive first-pass metabolism to form metabolites that are excreted in the bile. Therefore, little loperamide actually reaches the systemic circulation. The drug bioavailability is less than 1%. Following oral administration of a 2 mg capsule of loperamide, plasma concentrations of unchanged drug were below 2 ng/mL. Plasma loperamide concentrations are highest approximately five hours after administration of an oral capsule of loperamide and 2. 5 hours after the liquid formulation of the drug. The volume of distribution of Belantamab mafodotin is The mean steady state volume of distribution of belantamab mafodotin was 11 L. The volume of distribution of Loperamide is Loperamide has a large volume of distribution. Although highly lipophilic, loperamide does not cross the blood-brain barrier and generally acts peripherally. Belantamab mafodotin is Monoclonal antibodies are generally not protein bound. bound to plasma proteins. Loperamide is Based on literature information, the plasma protein binding of loperamide is about 95%. bound to plasma proteins. Belantamab mafodotin metabolism: Monoclonal antibodies are expected to be metabolized to smaller peptides and amino acids. MMAF is expected to be metabolized by oxidation and demethylation, however further data is not readily available. Loperamide metabolism: Loperamide is extensively metabolized. The primary metabolic pathway is oxidative N-demethylation mediated by CYP2C8 and CYP3A4, to form N-demethyl loperamide. CYP2B6 and CYP2D6 play a minor role in loperamide N-demethylation. Metabolites of loperamide are pharmacologically inactive. Belantamab mafodotin is eliminated via Monoclonal antibodies are eventually phagocytosed and broken down to smaller peptides and amino acids which are eliminated in a similar fashion to other proteins. Monoclonal antibodies are generally not eliminated in the urine, and only a small amount is excreted in bile. Loperamide is eliminated via Loperamide and its metabolites in the systemic circulation undergo biliary excretion. Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces. Only 1% of an absorbed dose excreted unchanged in the urine. The half-life of Belantamab mafodotin is The terminal half life of belantamab mafodotin was 12 days after the first dose and 14 days at steady state. The half-life of Loperamide is The apparent elimination half-life of loperamide is 10. 8 hours with a range of 9. 1 to 14. 4 hours. The clearance of Belantamab mafodotin is The clearance of belantamab mafodotin was 0. 9 L/day after the first dose and 0. 7 L/day at steady state. No clearance information is available for Loperamide. Belantamab mafodotin toxicity includes Data regarding overdose is not readily available. However, keratopathy was seen in 71% of patients. Loperamide toxicity includes Oral LD50 is 185 mg/kg in rats. Loperamide overdose can lead to a range of cardiac and non-cardiac effects. Chronic ingestion of doses ranging from 70 mg to 1600 mg daily - which is four to 100 times the recommended dose - resulted in life-threatening cardiac adverse reactions, including QT/QTc and QRS interval prolongation, Torsades de Pointes, Brugada syndrome and other ventricular arrhythmias, syncope, cardiac arrest, and death. These cases included instances of loperamide misuse and abuse. In case of cardiac effects, it is recommended that loperamide is discontinued and therapies to manage and prevent cardiac arrhythmias are initiated. Cases of loperamide overdose may cause opioid toxic effects including CNS depression (e. g. altered mental status, stupor, coordination disorders, somnolence, miosis, muscular hypertonia, respiratory depression), hypotension, urinary retention, and paralytic ileus. Naloxone may reverse the opioid-related toxicity, including CNS and respiratory depression, and hypotension, associated with loperamide overdosage. Brand names of Belantamab mafodotin include BLENREP. Brand names of Loperamide include Diamode, Imodium, Imodium Multi-symptom Relief. No synonyms are available for Belantamab mafodotin. No synonyms are available for Loperamide. Belantamab mafodotin summary: It is Belantamab mafodotin is an anti B-cell maturation antigen antibody conjugated to a microtubule inhibitor to treat relapsed or refractory multiple myeloma. Loperamide summary: It is Loperamide is a long acting antidiarrheal used to control nonspecific diarrhea and chronic diarrhea caused by inflammatory bowel disease, or gastroenteritis. Answer: The concomitant administration of two or more substrates of the p-gp transporter may result in the increased serum concentration of at least one or more of the substrates, due to competition among the substrates for the p-gp transporter. Depending on the p-gp substrate, this may result in drug toxicity and serious conditions such as excessive bleeding, cardiac conduction defects or organ toxicity, among many other effects.

Belantamab mafodotin

Drug A is Abiraterone. Drug B is Propafenone. The severity of the interaction is minor. The serum concentration of Propafenone can be increased when it is combined with Abiraterone. Abiraterone inhibits CYP1A2 3 and may interfere with the metabolism of the affected drug, which is metabolized by CYP1A2. Co-administration of two drugs may lead to a decrease in the metabolism of the affected drug, increasing serum concentrations as well as the risk and severity of adverse effects. Abiraterone is indicated for Abiraterone is indicated for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in combination with methylprednisolone or prednisone. In Europe and Canada, it is also used in patients with mCRPC who are asymptomatic or mildly symptomatic after the failure of androgen deprivation therapy for whom chemotherapy is not yet clinically indicated. In Europe, it is used in patients whose disease has progressed on or after a docetaxel-based chemotherapy regimen. In Canada, it is used in patients who have received prior chemotherapy containing docetaxel after the failure of androgen deprivation therapy. Abiraterone is indicated in combination with prednisone for the treatment of metastatic high-risk castration-sensitive prostate cancer (CSPC). In Europe and Canada, it may also be used in combination with prednisolone and androgen deprivation therapy in newly diagnosed patients. In Canada and the US, abiraterone is also available in a combination product with niraparib, which is indicated with prednisone for the treatment of adults with deleterious or suspected deleterious BRCA-mutated (BRCAm) mCRPC. In Canada, this combination product is also used with prednisolone and is reserved for patients who are asymptomatic or mildly symptomatic, and in whom chemotherapy is not clinically indicated. Propafenone is indicated for Used to prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease. Also used for the treatment of life-threatening documented ventricular arrhythmias, such as sustained ventricular tachycardia. Abiraterone pharmacodynamics: In vivo, abiraterone acetate is rapidly hydrolyzed to abiraterone, which mediates its pharmacological actions. Abiraterone decreases serum testosterone and other androgens. A change in serum prostate-specific antigen (PSA) levels may be observed. Propafenone pharmacodynamics: Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes. It is used in the treatment of atrial and ventricular arrhythmias. It acts by inhibiting sodium channels to restrict the entry of sodium into cardiac cells resulting in reduced excitation. Propafenone has local anesthetic activity approximately equal to procaine. The mechanism of action of Abiraterone is that it 17α-hydroxylase/C17,20-lyase (CYP17) is a key enzyme in androgen biosynthesis. It is primarily expressed in testicular, adrenal, and prostatic tumours. CYP17 catalyzes the 17α-hydroxylation of pregnenolone and progesterone to their 17α-hydroxy derivative, followed by subsequent cleavage of the C 20,21-acetyl group to yield dehydroepiandrosterone (DHEA) and androstenedione. DHEA and androstenedione are precursors of testosterone. Aberrant androgen levels and unregulated androgen receptor signalling have been implicated in the development and progression of various prostate cancers. Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Abiraterone inhibits CYP17 to block androgen production. Inhibition of CYP17 can also result in increased mineralocorticoid production by the adrenals. The mechanism of action of Propafenone is that it The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions, which is responsible for the drugs antiarrhythmic actions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Abiraterone absorption: Geometric mean (± SD) Cmax was 73 (± 44) ng/mL and AUC 0-∞ was 373 (± 249) ng x hr/mL following a single dose of 500 mg abiraterone acetate in overnight-fasted healthy subjects. Dose proportionality was observed in single doses of abiraterone acetate ranging from 125 mg to 625 mg. A group of patients with mCRPC received a daily dose of 1,000 mg: at steady-state, the mean (± SD) Cmax was 226 (± 178) ng/mL and AUC was 993 (± 639) ng x hr/mL. Following oral administration of abiraterone acetate to patients with metastatic castration-resistant prostate cancer, the median Tmax was two hours. In vivo, abiraterone acetate is converted to abiraterone. In clinical studies of other abiraterone acetate formulations, abiraterone acetate plasma concentrations were below detectable levels (< 0. 2 ng/mL) in > 99% of the analyzed samples. Systemic exposure to abiraterone is increased when abiraterone acetate is administered with food. Abiraterone Cmax was approximately 6. 5-fold higher, and AUC 0-∞ was 4. 4-fold higher when a single dose of abiraterone acetate 500 mg was administered with a high-fat meal (56-60% fat, 900-1,000 calories) compared to overnight fasting in healthy subjects. Given the normal variation in the content and composition of meals, taking abiraterone with meals has the potential to result in increased and highly variable exposures. Propafenone absorption: Nearly completely absorbed following oral administration (90%). Systemic bioavailability ranges from 5 to 50%, due to significant first-pass metabolism. This wide range in systemic bioavailability is related to two factors: presence of food (food increases bioavailability) and dosage (bioavailability is 3. 4% for a 150-mg tablet compared to 10. 6% for a 300-mg tablet). The volume of distribution of Abiraterone is The mean (± SD) apparent steady-state volume of distribution is 19,669 (± 13,358) L. The volume of distribution of Propafenone is 252 L. Abiraterone is Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. bound to plasma proteins. Propafenone is 97% bound to plasma proteins. Abiraterone metabolism: The conversion of abiraterone acetate to abiraterone, the active metabolite, is likely to be mediated by esterases, although specific esterases have not been identified. In human plasma, the two main circulating metabolites are abiraterone sulfate, which is formed by CYP3A4 and SULT2A1, and N-oxide abiraterone sulfate, which is formed by SULT2A1. These metabolites each account for about 43% of abiraterone exposure and are pharmacologically inactive. Propafenone metabolism: Metabolized primarily in the liver where it is rapidly and extensively metabolized to two active metabolites, 5-hydroxypropafenone and N-depropylpropafenone. These metabolites have antiarrhythmic activity comparable to propafenone but are present in concentrations less than 25% of propafenone concentrations. Abiraterone is eliminated via Following oral administration of C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces: the major compounds present in feces are unchanged abiraterone acetate and abiraterone, accounting for approximately 55% and 22% of the administered dose, respectively. Approximately 5% of the dose is recovered in urine. Propafenone is eliminated via Approximately 50% of propafenone metabolites are excreted in the urine following administration of immediate release tablets. The half-life of Abiraterone is In patients with mCRPC, the mean (± SD) terminal half-life of abiraterone in plasma is 12 (± 5) hours. The half-life of Propafenone is 2-10 hours. No clearance information is available for Abiraterone. No clearance information is available for Propafenone. Abiraterone toxicity includes The oral LD 50 is > 400 mg/kg in rats and 800 mg/kg in mice. The human experience of overdose with abiraterone is limited. Toxicity is related to the blockade of CYP17 activity. Blockade results in the accumulation of upstream mineralocorticoids like 11-deoxycorticosterone, leading to secondary hyperaldosteronism. Signs of hyperaldosteronism include fluid retention and hypokalemia. As there is no specific antidote for abiraterone overdose, overdosage should be managed with general supportive measures, including monitoring and assessment of cardiac and liver function. Propafenone toxicity includes Symptoms of propafenone overdose (usually most severe within the first 3 hours) may include convulsions (rarely), heartbeat irregularities, low blood pressure, and sleepiness. Brand names of Abiraterone include Yonsa, Zytiga. Brand names of Propafenone include Rythmol. No synonyms are available for Abiraterone. Abiraterone No synonyms are available for Propafenone. Propafenone Propafenonum Abiraterone summary: It is Abiraterone is an antiandrogen used in the treatment of metastatic castration-resistant prostate cancer and metastatic high-risk castration-sensitive prostate cancer. Propafenone summary: It is Propafenone is a Class 1C antiarrhythmic agent used in the management of paroxysmal atrial fibrillation/flutter and ventricular arrhythmias. Answer: Abiraterone inhibits CYP1A2 3 and may interfere with the metabolism of the affected drug, which is metabolized by CYP1A2. Co-administration of two drugs may lead to a decrease in the metabolism of the affected drug, increasing serum concentrations as well as the risk and severity of adverse effects.

Abiraterone

Drug A is Cetuximab. Drug B is Necitumumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Cetuximab is combined with Necitumumab. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Cetuximab is indicated for Cetuximab indicated for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy. It is indicated for treating a recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with fluorouracil. It is indicated for recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy. Cetuximab is also indicated for K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by an FDA-approved test in combination with FOLFIRI, a chemotherapy combination that includes leucovorin, fluorouracil, and irinotecan; in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy; or as monotherapy in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. Additionally, cetuximab is also indicated for metastatic colorectal cancer that is BRAF V600E mutation-positive (as determined by an FDA-approved test) in combination with encorafenib but only after prior therapy. Cetuximab is not indicated for the treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown. Necitumumab is indicated for Necitumumab is approved for use in combination with cisplatin and gemcitabine as a first-line treatment for metastatic squamous non-small cell lung cancer (NSCLC). It is not indicated for treatment of non-squamous NSCLC. Cetuximab pharmacodynamics: Cetuximab is an anticancer agent that works by inhibiting the growth and survival of epidermal growth factor receptor (EGFR)-expressing tumour cells with high specificity and higher affinity than epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α), which are natural ligands of EGFR. Cetuximab works by inhibiting the growth and survival of EGFR-positive tumours. In vitro, it promotes antibody-dependent cellular cytotoxicity (ADCC) against certain human tumour types. On the contrary, cetuximab does not exert its anti-tumour effects on human tumour xenografts lacking EGFR expression. Cetuximab potentiates the cytotoxic effects of chemotherapeutics and radiation therapy when used in combination. In human tumour xenograft models in mice, cetuximab and irinotecan synergistically inhibited the growth of orthotopic anaplastic thyroid carcinoma xenografts in vitro and in vivo. Cetuximab potentiated the in vitro anti-proliferative and pro-apoptotic effect of irinotecan and achieved 93% in vivo inhibition of tumour growth when combined with irinotecan, compared to 77% and 79% inhibition when cetuximab and irinotecan were used alone, respectively. Necitumumab pharmacodynamics: No pharmacodynamics available. The mechanism of action of Cetuximab is that it The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein and a type I receptor tyrosine kinase expressed on both normal and malignant cells. It has been investigated as a therapeutic target for anticancer treatment, as it is often upregulated in cancer types, including head and neck, colon, and rectal cancers. When activated by its ligand, EGFR undergoes a conformational change and dimerization to form homodimers or heterodimers with another member of the ErbB family of receptors. Dimerization of EGFR activates the intracellular tyrosine kinase region of EGFR and promotes autophosphorylation, initiating a series of downstream signalling cascades, including cell differentiation, proliferation, migration, angiogenesis, and apoptosis. This EGFR signalling pathway is often dysregulated in cancer cells, leading to aberrant cell growth and enhanced cell survival. Cetuximab is a monoclonal antibody that binds specifically to the EGFR on both normal and tumour cells to competitively inhibit the binding of epidermal growth factor (EGF) and other ligands that are produced by normal and tumour tissue epithelial cells. Upon binding to domain III of EGFR - which is the binding site for its growth factor ligands - cetuximab prevents the receptor from adopting an extended conformation and thereby inhibits EGFR activation, as well as phosphorylation and activation of receptor-associated kinases (MAPK, PI3K/Akt, Jak/Stat). Inhibition of the EGFR signalling pathway ultimately leads to inhibition of cell cycle progression, cell survival pathways, and tumour cell motility and invasion. Cetuximab also induces cell apoptosis and decreases matrix metalloproteinase and vascular endothelial growth factor (VEGF) production. In vitro, cetuximab was shown to inhibit tumour angiogenesis. Binding of cetuximab to EGFR also results in internalization of the antibody-receptor complex, leading to an overall downregulation of EGFR expression. K-ras is a small G-protein downstream of EGFR that plays an important role in promoting the EGFR signalling cascade: in some malignant cells, K-ras can acquire activating mutations in exon 2 and thus be continuously active regardless of EGFR regulation. Since mutant Ras proteins can isolate the pathway from the effect of EGFR, K-Ras mutations can render EGFR inhibitors like cetuximab ineffective in exerting anti-tumour effects. Cetuximab is thus only limited in its use for K-Ras wild-type, EGFR-expressing cancers. The mechanism of action of Necitumumab is that it Necitumumab is an EGFR antagonist that functions by binding to epidermal growth factor receptor (EGFR) and preventing binding of its ligands, a process that is involved in cell proliferation, metastasis, angiogenesis, and malignant progression. Binding of necitumumab to EGFR induces receptor internalization and degradation. Cetuximab absorption: After administration of a 400 mg/m initial dose followed by a 250 mg/m weekly dose, the steady-state levels of cetuximab was reached by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 µg/mL to 235 µg/mL and 41 µg/mL to 85 µg/mL, respectively. Tmax is about 3 hours. No absorption information is available for Necitumumab. The volume of distribution of Cetuximab is The volume of the distribution is about 2-3 L/m and is independent of dose. The volume of distribution of Necitumumab is Steady state volume of distribution is 7. 0 L. Cetuximab is There is no information available. bound to plasma proteins. No protein binding information is available for Necitumumab. Cetuximab metabolism: Like other monoclonal antibodies, cetuximab is expected to undergo lysosomal degradation by the reticuloendothelial system and protein catabolism by a target‐mediated disposition pathway. No metabolism information is available for Necitumumab. Cetuximab is eliminated via There is limited information available. Necitumumab is eliminated via No route of elimination available. The half-life of Cetuximab is After administration of a 400 mg/m initial dose followed by a 250 mg/m weekly dose, the mean half-life for cetuximab was approximately 112 hours, with a range of 63 to 230 hours. The half-life of Necitumumab is Elimination half life is approximately 14 days. The clearance of Cetuximab is In patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, the estimated clearance rate was 0. 103 L/h. At doses ranging from 200 to 400 mg/m, complete saturation of systemic clearance was observed. In a population pharmacokinetic study, female patients had a 25% lower intrinsic cetuximab clearance than male patients, although there was no evidence of the need for dose modification based on sex. The clearance of Necitumumab is 14. 1 mL/h. Cetuximab toxicity includes The intravenous LD 50 is > 300 mg/kg in mice and > 200 mg/kg in rats. There is limited information on the overdose from cetuximab. In clinical trials, cetuximab was associated with serious and fatal infusion reactions, cardiopulmonary arrest or sudden death, and serious dermatologic toxicities. Pulmonary toxicities, such as interstitial lung disease, interstitial pneumonitis with non-cardiogenic pulmonary edema, and exacerbation of pre-existing fibrotic lung disease have been reported. Necitumumab toxicity includes The poor safety profile of necitumumab has been one of the major limitations of its use. Rigorous monitoring of the following adverse events is recommended for the use of this drug: cardiopulmonary arrest, hypomagnesia, venous and arterial thromboembolic events, dermatologic toxicities, and infusion-related reactions. Due to observations of increased toxicity and mortality in treatment of non-squamous NSCLC, necitumumab is only recommended for the treatment of squamous NSCLC in combination with cisplatin and gemcitabine. Animal studies suggest potential embryo-fetal toxicity. Brand names of Cetuximab include Erbitux. Brand names of Necitumumab include Portrazza. No synonyms are available for Cetuximab. No synonyms are available for Necitumumab. Cetuximab summary: It is Cetuximab is an endothelial growth factor receptor binding fragment used to treat colorectal cancer as well as squamous cell carcinoma of the head and neck. Necitumumab summary: It is Necitumumab is a monoclonal antibody used to treat metastatic squamous non-small cell lung cancer. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Cetuximab

Drug A is Corticotropin. Drug B is Tacrolimus. The severity of the interaction is moderate. Tacrolimus may increase the immunosuppressive activities of Corticotropin. Tacrolimus is an immunosuppressant with a potential to induce infections, lymphoma and other malignancies, particularly with long-term use. The concomitant use of tacrolimus with other immunosuppressive agents may create an additive effect and lead to an increased risk of immunosuppression-related adverse reactions. Corticotropin is indicated for use as a diagnostic agent in the screening of patients presumed to have adrenocortical insufficiency. Purified corticotropin for injection is indicated for a variety of allergic and autoimmune conditions. Tacrolimus is indicated for Immediate-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants. Extended-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving kidney transplants, in combination with other immunosuppressants, and may be used in patients converted from immediate-release formulations. Topical tacrolimus ointment is indicated as second-line therapy for short-term and non-continuous treatment of moderate-to-severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical treatments or for whom alternative treatments are not advisable. Both available strengths are indicated in adult patients, while only the lower strength (0. 03%) formulation is indicated in pediatric patients between 2 and 15 years of age. Corticotropin pharmacodynamics: Corticotropin acts through the stimulation of cell surface ACTH receptors, which are primarily located on the adrenocortical cells. Corticotropin stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainly glucocorticoids but also sex steroids (androgens). Corticotropin is also related to the circadian rhythm in many organisms. Tacrolimus pharmacodynamics: Tacrolimus acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Tacrolimus has similar activity to cyclosporine but rates of rejection are lower with tacrolimus. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment. The mechanism of action of Corticotropin is that it As a diagnostic aid (adrenocortical function), corticotropin combines with a specific receptor on the adrenal cell plasma membrane. In patients with normal adrenocortical function, it stimulates the initial reaction involved in the synthesis of adrenal steroids (including cortisol, cortisone, weak androgenic substances, and a limited quantity of aldosterone) from cholesterol by increasing the quantity of cholesterol within the mitochondria. Corticotropin does not significantly increase serum cortisol concentrations in patients with primary adrenocortical insufficiency (Addison's disease). The mechanism of action of corticotropin in the treatment of infantile myoclonic seizures is unknown. The mechanism of action of Tacrolimus is that it The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells. Corticotropin absorption: Corticotropin is rapidly absorbed following intramuscular administration; the repository dosage form is slowly absorbed over approximately 8 to 16 hours. Tacrolimus absorption: Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1. 5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. No volume of distribution information is available for Corticotropin. The volume of distribution of Tacrolimus is 2. 6 ± 2. 1 L/kg [pediatric liver transplant patients]. 1. 07 ± 0. 20 L/kg [patients with renal impairment, 0. 02 mg/kg/4 hr dose, IV] 3. 1 ± 1. 6 L/kg [Mild Hepatic Impairment, 0. 02 mg/kg/4 hr dose, IV] 3. 7 ± 4. 7 L/kg [Mild Hepatic Impairment, 7. 7 mg dose, PO] 3. 9 ± 1. 0 L/kg [Severe hepatic impairment, 0. 02 mg/kg/4 hr dose, IV] 3. 1 ± 3. 4 L/kg [Severe hepatic impairment, 8 mg dose, PO] No protein binding information is available for Corticotropin. Tacrolimus is ~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL. bound to plasma proteins. No metabolism information is available for Corticotropin. Tacrolimus metabolism: The metabolism of tacrolimus is predominantly mediated by CYP3A4 and secondarily by CYP3A5. Tacrolimus is metabolized into 8 metabolites: 13-demethyl tacrolimus, 31-demethyl tacrolimus, 15-demethyl tacrolimus, 12-hydroxy tacrolimus, 15,31-didemethyl tacrolimus, 13,31-didemethyl tacrolimus, 13,15-didemethyl tacrolimus, and a final metabolite involving O-demethylation and the formation of a fused ring. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. Corticotropin is eliminated via No route of elimination available. Tacrolimus is eliminated via In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92. 6±30. 7%, urinary elimination accounted for 2. 3±1. 1%. The half-life of Corticotropin is About 15 minutes following intravenous administration. The half-life of Tacrolimus is The elimination half life in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11. 5±3. 8 hours, in pediatric kidney transplant patients was 10. 2±5. 0 (range 3. 4-25) hours. No clearance information is available for Corticotropin. The clearance of Tacrolimus is 0. 040 L/hr/kg [healthy subjects, IV]. 0. 172 ± 0. 088 L/hr/kg [healthy subjects, oral] 0. 083 L/hr/kg [adult kidney transplant patients, IV] 0. 053 L/hr/kg [adult liver transplant patients, IV] 0. 051 L/hr/kg [adult heart transplant patients, IV] 0. 138 ± 0. 071 L/hr/kg [pediatric liver transplant patients] 0. 12 ± 0. 04 (range 0. 06-0. 17) L/hr/kg [pediatric kidney transplant patients] 0. 038 ± 0. 014 L/hr/kg [patients with renal impairment, 0. 02 mg/kg/4 hr dose, IV] 0. 042 ± 0. 02 L/hr/kg [Mild Hepatic Impairment, 0. 02 mg/kg/4 hr dose, IV] 0. 034 ± 0. 019 L/hr/kg [Mild Hepatic Impairment, 7. 7 mg dose, PO] 0. 017 ± 0. 013 L/hr/kg [Severe hepatic impairment, 0. 02 mg/kg/4 hr dose, IV] 0. 016 ± 0. 011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO] No toxicity information is available for Corticotropin. Tacrolimus toxicity includes Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD 50 =134-194 mg/kg (rat). Brand names of Corticotropin include Acthar, Cortrophin. Brand names of Tacrolimus include Advagraf, Astagraf, Envarsus, Modigraf, Prograf, Protopic. No synonyms are available for Corticotropin. No synonyms are available for Tacrolimus. Corticotropin summary: It is Corticotropin is a diagnostic agent used in the screening of patients presumed to have adrenocortical insufficiency. Tacrolimus summary: It is Tacrolimus is a calcineurin inhibitor used to prevent organ transplant rejection and to treat moderate to severe atopic dermatitis. Answer: Tacrolimus is an immunosuppressant with a potential to induce infections, lymphoma and other malignancies, particularly with long-term use. The concomitant use of tacrolimus with other immunosuppressive agents may create an additive effect and lead to an increased risk of immunosuppression-related adverse reactions.

Corticotropin

Drug A is Bimekizumab. Drug B is Lornoxicam. The severity of the interaction is moderate. The metabolism of Lornoxicam can be increased when combined with Bimekizumab. The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. Bimekizumab is indicated for Bimekizumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Lornoxicam is indicated for the treatment of acute mild to moderate pain, as well as pain and inflammation of the joints caused by certain types of rheumatic diseases. Bimekizumab pharmacodynamics: Bimekizumab exerts its pharmacologic effects by binding to and inhibiting one of the pro-inflammatory cytokines involved in psoriasis pathogenesis. It is administered once-monthly as a subcutaneous injection. Bimekizumab may increased the risk of infection, including upper respiratory tract infections and oral candidiasis. Any clinically important active infections should be resolved prior to therapy. In addition, the use of live vaccines during bimekizumab therapy is not recommended - ensure patients beginning therapy have completed all age appropriate immunizations prior to initiation. Lornoxicam pharmacodynamics: Lornoxicam is a non-steroidal anti-inflammatory drug (NSAID) that belongs to the oxicam class. As with other NSAIDS, lornoxicam is a potent inhibitor of the cyclooxgenase enzymes, which are responsible for catalyzing the formation of prostaglandins (act as messenger molecules in the process of inflammation) and thromboxane from arachidonic acid. Unlike some NSAIDS, lornoxicam's inhibition of cyclooxygenase does not lead to an increase in leukotriene formation, meaning that arachidonic acid is not moved to the 5-lipoxygenase cascade, resulting in the minimization of the risk of adverse events. The mechanism of action of Bimekizumab is that it The pathophysiology of psoriasis involves a dysregulation of the immune system and is facilitated by a variety of cytokines released by dendritic cells and T-helper cells. Plaque psoriasis, the most common subtype of psoriasis, is driven primarily by tumor necrosis factor-alpha (TNF-α) and interleukins 17 and 23 (IL-17 and IL-23), with the axis between these three cytokines integral to the maintenance phase of psoriasis. IL-17 acts through two separate mechanisms: the first, dependent on the cytoplasmic adaptor protein ACT1, involves the activation of NF-κB and the transcription of inflammatory genes. The second, independent of ACT1, involves the activation of the JAK/STAT signaling cascade, which leads to further transcription of pro-inflammatory proteins and continued psoriasis pathogenicity. Bimekizumab is a monoclonal antibody targeted against IL-17A, IL-17F, and a heterodimer of the two called IL-17AF. It blocks the interaction of these interleukins with their respective receptors, thus reducing psoriatic inflammation. The mechanism of action of Lornoxicam is that it Like other NSAIDS, lornoxicam's anti-inflammatory and analgesic activity is related to its inhibitory action on prostaglandin and thromboxane synthesis through the inhibition of both COX-1 and COX-2. This leads to the reduction of inflammation, pain, fever, and swelling, which are mediated by prostaglandins. However, the exact mechanism of lornoxicam, like that of the other NSAIDs, has not been fully determined. Bimekizumab absorption: In healthy volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70. 1%. Lornoxicam absorption: Lornoxicam is absorbed rapidly and almost completely from the GI tract (90-100%). The volume of distribution of Bimekizumab is In patients with plaque psoriasis, the median volume of distribution at steady-state was 11. 2 L. No volume of distribution information is available for Lornoxicam. No protein binding information is available for Bimekizumab. Lornoxicam is Lornoxicam is 99% bound to plasma proteins (almost exlusively to serum albumin). bound to plasma proteins. Bimekizumab metabolism: As a monoclonal antibody, bimekizumab is likely degraded into smaller peptides and amino acids via catabolic processes. Lornoxicam metabolism: Lornoxicam is metabolized completely by cyp 2C9 with the principal metabolite being 5'-hydroxy-lornoxicam and only negligible amounts of intact lornoxicam are excreted unchanged in the urine. Approximately 2/3 of the drug is eliminated via the liver and 1/3 via the kidneys in the active form. Bimekizumab is eliminated via No route of elimination available. Lornoxicam is eliminated via No route of elimination available. The half-life of Bimekizumab is The mean terminal elimination half-life of bimekizumab in patients with plaque psoriasis was 23 days. The half-life of Lornoxicam is 3-5 hours. The clearance of Bimekizumab is The median apparent clearance of bimekuzmab in patients with plaque psoriasis was 0. 337 L/day. No clearance information is available for Lornoxicam. Bimekizumab toxicity includes Single doses of up to 640mg given both intravenously and subcutaneously have been administered in clinical studies without evidence of dose-limiting toxicities. If overdosage of bimekizumab is suspected, monitor the patient for adverse reactions and institute symptomatic treatment as clinically indicated. No toxicity information is available for Lornoxicam. Brand names of Bimekizumab include No brand names available. Brand names of Lornoxicam include No brand names available. No synonyms are available for Bimekizumab. No synonyms are available for Lornoxicam. Bimekizumab summary: It is Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment plaque psoriasis. Lornoxicam summary: It is Lornoxicam is an NSAID indicated in the treatment of mild to moderate pain, as well as rheumatoid arthritis and osteoarthritis. Answer: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates.

Bimekizumab

Drug A is Budesonide. Drug B is Venlafaxine. The severity of the interaction is minor. Venlafaxine may decrease the excretion rate of Budesonide which could result in a higher serum level. The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes, they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. Budesonide is indicated for Budesonide extended-release capsules are indicated for the treatment and maintenance of mild to moderate Crohn’s disease. Various inhaled budesonide products are indicated for prophylactic therapy in asthma and to reduce exacerbations of COPD. A budesonide nasal spray is available over the counter for symptoms of hay fever and upper respiratory allergies. Extended-release capsules are indicated to induce remission of mild to moderate ulcerative colitis and a rectal foam is used for mild to moderate distal ulcerative colitis. In addition, a delayed-release capsule formulation of budesonide is indicated to reduce proteinuria in adults with IgA nephropathy at risk of rapid disease progression. Budesonide is indicated to treat eosinophilic esophagitis (EoE): For this indication, it is only approved for use in adults in Europe while it is approved for short-term use (12 weeks) in patients 11 years of age and older in the US. Venlafaxine is indicated for Venlafaxine is indicated for the management of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder. Budesonide pharmacodynamics: Budesonide is a glucocorticoid used to treat respiratory and digestive conditions by reducing inflammation. It has a wide therapeutic index, as dosing varies highly from patient to patient. Patients should be counselled regarding the risk of hypercorticism and adrenal axis suppression. Venlafaxine pharmacodynamics: Venlafaxine is an antidepressant agent that works to ameliorate the symptoms of various psychiatric disorders by increasing the level of neurotransmitters in the synapse. Venlafaxine does not mediate muscarinic, histaminergic, or adrenergic effects. The mechanism of action of Budesonide is that it The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. The mechanism of action of Venlafaxine is that it The exact mechanism of action of venlafaxine in the treatment of various psychiatric conditions has not been fully elucidated; however, it is understood that venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) potently and selectively inhibits the reuptake of both serotonin and norepinephrine at the presynaptic terminal. This results in increased levels of neurotransmitters available at the synapse that can stimulate postsynaptic receptors. It is suggested that venlafaxine has a 30-fold selectivity for serotonin compared to norepinephrine: venlafaxine initially inhibits serotonin reuptake at low doses, and with higher doses, it inhibits norepinephrine reuptake in addition to serotonin. Venlafaxine and ODV are also weak inhibitors of dopamine reuptake. Budesonide absorption: Extended release oral capsules are 9-21% bioavailable. A 9mg dose reaches a Cmax of 1. 50±0. 79ng/mL with a Tmax of 2-8h and an AUC of 7. 33ng*hr/mL. A high fat meal increases the Tmax by 2. 3h but otherwise does not affect the pharmacokinetics of budesonide. 180-360µg metered inhaled doses of budesonide are 34% deposited in the lungs, 39% bioavailable, and reach a Cmax of 0. 6-1. 6nmol/L with a Tmax of 10 minutes. A 1mg nebulized dose is 6% bioavailable, reaching a Cmax of 2. 6nmol/L with a Tmax of 20 minutes. A 9mg oral extended release tablet reaches a Cmax of 1. 35±0. 96ng/mL with a Tmax of 13. 3±5. 9h and an AUC of 16. 43±10. 52ng*hr/mL. Budesonide rectal foam 2mg twice daily has an AUC of 4. 31ng*hr/mL. Venlafaxine absorption: Venlafaxine is well absorbed after oral administration with an absolute bioavailability of approximately 45%. In mass balance studies, at least 92% of a single oral dose of venlafaxine was absorbed. After twice-daily oral administration of immediate-release formulation of 150 mg venlafaxine, Cmax was 150 ng/mL and Tmax was 5. 5 hours. Cmax and Tmax of ODV were 260 ng/mL and nine hours, respectively. The extended-release formulation of venlafaxine has a slower rate of absorption, but the same extent of absorption as the immediate-release formulation. After once-daily administration of extended-release formulation of 75 mg venlafaxine, Cmax was 225 ng/mL and Tmax was two hours. Cmax and Tmax of ODV were 290 ng/mL and three hours, respectively. Food does not affect the bioavailability of venlafaxine or its active metabolite, O-desmethylvenlafaxine (ODV). The volume of distribution of Budesonide is The volume of distribution of budesonide is 2. 2-3. 9L/kg. The volume of distribution of Venlafaxine is The apparent volume of distribution at steady-state is 7. 5 ± 3. 7 L/kg for venlafaxine and 5. 7 ± 1. 8 L/kg for ODV. Budesonide is Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. Budesonide is 85-90% protein bound in plasma. bound to plasma proteins. Venlafaxine is Venlafaxine and ODV is 27% and 30% bound to plasma proteins, respectively. bound to plasma proteins. Budesonide metabolism: Budesonide is 80-90% metabolized at first pass. Budesonide is metabolized by CYP3A to its 2 major metabolites, 6beta-hydroxybudesonide and 16alpha-hydroxyprednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. CYP3A4 is the strongest metabolizer of budesonide, followed by CYP3A5, and CYP3A7. Venlafaxine metabolism: Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. It primarily undergoes CYP2D6-mediated demethylation to form its active metabolite O-desmethylvenlafaxine (ODV). Venlafaxine can also undergo N-demethylation mediated by CYP2C9, and CYP2C19, and CYP3A4 to form N-desmethylvenlafaxine (NDV) but this is a minor metabolic pathway. ODV and NDV further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to form N,O-didesmethylvenlafaxine (NODV) and NODV can be further metabolized to form N, N, O-tridesmethylvenlafaxine, followed by a possible glucuronidation. Budesonide is eliminated via Approximately 60% of a budesonide dose is recovered in the urine as the major metabolites 6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone, and their conjugates. No unchanged budesonide is recovered in urine. Venlafaxine is eliminated via Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). The half-life of Budesonide is Budesonide has a plasma elimination half life of 2-3. 6h. The terminal elimination half life in asthmatic children 4-6 years old is 2. 3h. The half-life of Venlafaxine is The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV. The clearance of Budesonide is Budesonide has a plasma clearance of 0. 9-1. 8L/min. The 22R form has a clearance of 1. 4L/min while the 22S form has a clearance of 1. 0L/min. The clearance in asthmatic children 4-6 years old is 0. 5L/min. The clearance of Venlafaxine is Mean ± SD plasma apparent clearance at steady-state is 1. 3 ± 0. 6 L/h/kg for venlafaxine and 0. 4 ± 0. 2 L/h/kg for ODV. Budesonide toxicity includes Acute overdose of corticosteroids is rare, however prolonged high dosing of corticosteroids can lead to hypercorticism and adrenal axis suppression. In the case of overdose, reduce the dosage of corticosteroids temporarily. A 200mg oral dose is lethal to female mice while a 400mg oral dose is lethal to male mice. Venlafaxine toxicity includes Oral LD 50 was 350 mg/kg in female rats and 700 mg/kg in male rats. There are reports of acute overdosage with venlafaxine either alone or in combination with other drugs including alcohol. Doses up to several-fold higher than the usual therapeutic dose have been ingested in these cases of acute overdosage. Somnolence is the most commonly reported symptom, along with other symptoms such as paresthesia of the extremities, moderate dizziness, altered consciousness, nausea, vomiting, numb hands and feet, hot-cold spells (which occur a few days after the overdose event), hypotension, convulsions, sinus and ventricular tachycardia, rhabdomyolysis, vertigo, liver necrosis, electrocardiogram changes (e. g., prolongation of QT interval, bundle branch block, QRS prolongation), serotonin syndrome, and death. There is no known antidote for venlafaxine overdose. Cases of overdose have been managed with or without symptomatic treatment, hospitalization, and activated charcoal. Retrospective studies suggest that the risk of fatal outcomes from venlafaxine overdosage is higher than that of SSRI antidepressants, but lower than that of tricyclic antidepressants. Brand names of Budesonide include Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris. Brand names of Venlafaxine include Effexor. No synonyms are available for Budesonide. Budesonide No synonyms are available for Venlafaxine. Budesonide summary: It is Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis. Venlafaxine summary: It is Venlafaxine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for the treatment of major depression, generalized or social anxiety disorder, and panic disorder. Answer: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

Budesonide

Drug A is Omalizumab. Drug B is Digoxin Immune Fab (Ovine). The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Omalizumab is combined with Digoxin Immune Fab (Ovine). Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Omalizumab is indicated for This drug is an anti-IgE antibody indicated for: Moderate to severe persistent asthma in patients 6 years of age and older. with a positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids Chronic idiopathic urticaria in adults and adolescents 12 years of age and older who remain symptomatic despite H1 antihistamine treatment Digoxin Immune Fab (Ovine) is indicated for treatment of digitoxin overdose or digitalis glycoside toxicity. Omalizumab pharmacodynamics: Omalizumab is a recombinant, humanized, monoclonal antibody against human immunoglobulin E (IgE) which treats the symptoms of asthma and chronic idiopathic urticaria by limiting the allergic response,. It inhibits the binding of IgE to receptors on mast cells and basophils, blocking the IgE-mediated secretion of inflammatory mediators from these cells. Mast cell activation and the release of mediators, in response to allergen exposure and IgE, results in a cascade of events. This cascade culminates in the activation of B-lymphocytes, T-lymphocytes, eosinophils, fibroblasts, smooth muscle cells, and the endothelium. This cellular interaction, as well as the release of cytokines, chemokines and growth factors and inflammatory remodeling of the airway results in chronic asthma. After 4 weeks of use of this medication in patients with chronic urticaria, it was found that rescue medication use was reduced significantly and quality of life improved. Digoxin Immune Fab (Ovine) pharmacodynamics: DigiFab binds molecules of digoxin, making them unavailable for binding at their site of action on cells in the body. The Fab fragment-digoxin complex accumulates in the blood, from which it is excreted by the kidney. The net effect is to shift the equilibrium away from binding of digoxin to its receptors in the body, thereby reversing its effects. The mechanism of action of Omalizumab is that it When an environmental allergen first enters the body, is taken up by antigen-presenting cells (APCs). It is then processed, and presented to T and B immune cells. This is followed by the activation of B-lymphocyte and production of allergen-specific IgE. This IgE is then released by plasma cells (converted B lymphocytes) and is therefore available to bind to IgE receptors on several other cells. IgE binds to high-affinity (Fc€RI) and low-affinity (Fc€RII) receptors on multiple cells of the immune system. Following subsequent antigen exposure, cross-linking of the antigen occurs by several Fc€RI-bound IgE molecules on the surface of both basophils and mast cells. This leads to the activation of mast cells and histamine release, producing a wheal and other symptoms of urticaria. The following are explanations of the mechanism of action for both indications of this drug: Asthma Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of both mast cells and basophils. The reduction in surface-bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the typical allergic response. Treatment with omalizumab also reduces the number of FcεRI receptors on basophils in atopic patients. Omalizumab binds to free IgE with a higher affinity than IgE itself binds to the high-affinity Fc€RI receptors found on basophils. Therefore, it decreases the availability of free IgE for binding. Omalizumab by itself does not bind to the Fc€RI receptors, nor does the drug bind to receptor-bound IgE. These binding characteristics allow omalizumab to neutralize the typical IgE-mediated responses without causing the degranulation of basophils or cross-linking with basophil-bound IgE. Chronic Idiopathic Urticaria Omalizumab binds to IgE and decreases free IgE levels. Subsequently, IgE receptors (FcεRI) on cells are down-regulated. The mechanism by which these effects of omalizumab result in an improvement of CIU symptoms is unclear. The mechanism of action of Digoxin Immune Fab (Ovine) is that it Binds excess digoxin or digitoxin molecules circulating in the blood. Omalizumab absorption: After subcutaneous administration in pharmacokinetic studies, omalizumab was absorbed with a mean absolute bioavailability of 62%. After the administration of a single subcutanous dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly. The peak serum concentrations peaked after an average of 7­-8 days. In patients with CIU, the peak serum concentration was reached at a similar time after a single SC dose. The pharmacokinetics of omalizumab was linear at doses which were higher than 0. 5 mg/kg. In patients with asthma, after several doses of omalizumab, areas under the serum concentration-time curve from Day 0 to Day 14 at steady state were up to 6-fold of those after one dose. In patients with CIU, omalizumab showed linear pharmacokinetics in the dose range of 75 mg to 600 mg administered as a single subcutaneous dose. After repeated dosing from 75mg-300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose. No absorption information is available for Digoxin Immune Fab (Ovine). The volume of distribution of Omalizumab is The apparent volume of distribution of omalizumab in patients with asthma after subcutaneous administration was 78 ± 32 mL/kg. In patients with CIU, the distribution of omalizumab was similar to that in asthmatic patients. The volume of distribution of Digoxin Immune Fab (Ovine) is 0. 3 L/kg [DigiFab]. 0. 4 L/kg [Digibind] Omalizumab is Monoclonal antibodies are usually not required to have protein binding studies. bound to plasma proteins. No protein binding information is available for Digoxin Immune Fab (Ovine). Omalizumab metabolism: Monoclonal antibodies, in general, are believed to be internalized in endothelial cells bound to the Fc receptor and rescued from metabolism by recycling. At a later time, they are degraded in the reticuloendothelial system to smaller peptides and amino acids, which can then be used for de-novo protein synthesis. Several factors may influence this process, however. These include factors related to the target antigen, antibody, and patient. The metabolism of omalizumab is determined by its IgG1 framework, and by its specific binding to IgE. The elimination of omalizumab is dose-dependent. The reticuloendothelial system and the liver are two sites of elimination for IgG (including degradation in the liver reticuloendothelial system and endothelial cells),. The omalizumab:IgE complexes are thought to be to cleared via interactions with Fc- gamma-Rs (Fc gamma RI, Fc gamma RII, and Fc gamma RIII) at rates that are more rapid than that of IgG clearance. The relative clearance of free omalizumab, free IgE, and complexes is summarized as: free IgE clearance > > omalizumab:IgE clearance > omalizumab clearance. No metabolism information is available for Digoxin Immune Fab (Ovine). Omalizumab is eliminated via Liver elimination of IgG includes degradation in the liver reticuloendothelial system (RES) and endothelial cells. Intact IgG was also shown to be excreted in bile, in pharmacokinetic studies. Digoxin Immune Fab (Ovine) is eliminated via Cumulative urinary excretion of digoxin was comparable for both products and exceeded 40% of the administered dose by 24 hours. The half-life of Omalizumab is In chronic idiopathic urticaria (CIU) patients, at steady state, based on population pharmacokinetics, omalizumab serum elimination half-life averaged 24 days. In asthmatic patients omalizumab serum elimination half-life averaged 26 days. The half-life of Digoxin Immune Fab (Ovine) is 15-20 hrs. The clearance of Omalizumab is In pharmacokinetic studies, the clearance of omalizumab involved IgG clearance as well as clearance by specific binding and complex formation with its target ligand, IgE,. The apparent clearance averaging 2. 4 ± 1. 1 mL/kg/day was measured in asthmatic patients. In chronic idiopathic urticaria (CIU) patients, at steady state, based on population pharmacokinetics, omalizumab apparent clearance averaged 240 mL/day (corresponding to 3. 0 mL/kg/day for an 80 kg patient). No clearance information is available for Digoxin Immune Fab (Ovine). Omalizumab toxicity includes Anaphylaxis may occur rarely with this agent, either after the first dose or multiple doses,. Anaphylaxis presenting clinically as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, has been reported during and after this use of this drug. Therefore, close clinical monitoring should be performed during and shortly after administration. Maximum Dosage The maximum tolerated dosage of omalizumab has not yet been determined. Single intravenous (IV) doses of up to 4000 mg have been administered to patients without evidence of dose-limiting toxicity. The highest cumulative dose administered to patients was 44,000 mg over a 20 week time period, which was not associated with any toxicities. The use in Pregnancy The data with omalizumab use in pregnant women are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as omalizumab, are transported across the placenta in a linear fashion as a pregnancy progresses; therefore, potential effects on a fetus are likely to be greater in frequency during the second and third trimesters. In women with inadequately or moderately controlled asthma, the current evidence suggests that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small fetal size. The use During Breastfeeding There is no information regarding the presence of omalizumab in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for omalizumab and any potential adverse effects on the breastfed child from omalizumab or from the underlying maternal condition. No toxicity information is available for Digoxin Immune Fab (Ovine). Brand names of Omalizumab include Xolair. Brand names of Digoxin Immune Fab (Ovine) include Digifab. No synonyms are available for Omalizumab. No synonyms are available for Digoxin Immune Fab (Ovine). Omalizumab summary: It is Omalizumab is a monoclonal anti-immunoglobulin E antibody used in the treatment of severe asthma and chronic idiopathic urticaria. Digoxin Immune Fab (Ovine) summary: It is Digoxin Immune Fab (Ovine) is an antibody binding fragment which binds digoxin molecules which is used as an antidote to digoxin overdose. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Omalizumab

Drug A is Certolizumab pegol. Drug B is Amoxicillin. The severity of the interaction is minor. Amoxicillin may decrease the excretion rate of Certolizumab pegol which could result in a higher serum level. The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes, they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. Certolizumab pegol is indicated for Certolizumab pegol has been approved for several different conditions listed below: Symptomatic management of Chron's disease patients and for the maintenance of clinical response in patients with moderate to severe disease with inadequate response to conventional therapy. Treatment of adult patients with moderate to severely active rheumatoid arthritis. Treatment of adult patients with active psoriatic arthritis. Treatment of adult patients with active ankylosing spondylitis. Treatment of adult patients with moderate-to-severe plaque psoriasis that are candidates for systemic therapy or phototherapy. Treatment of adult patients with active non-radiographic axial spondyloarthritis with objective signs of inflammation. In Canada, certolizumab pegol is additionally approved in combination with methotrexate for the symptomatic treatment, including major clinical response, and for the reduction of joint damage in adult patients with moderately to severely active rheumatoid arthritis and psoriatic arthritis. Inflammation is a biological response against a potential threat. This response can be normal but in certain conditions, the immune system can attack the body's normal cells or tissues which causes an abnormal inflammation. TNF-alpha has been identified as a key regulator of the inflammatory response. The signaling cascades of this inflammatory mediator can produce a wide range of reactions including cell death, survival, differentiation, proliferation and migration. Amoxicillin is indicated for Amoxicillin alone is indicated to treat susceptible bacterial infections of the ear, nose, throat, genitourinary tract, skin, skin structure, and lower respiratory tract. Amoxicillin is given with calvulanic acid to treat acute bacterial sinusitis, community acquired pneumonia, lower respiratory tract infections, acute bacterial otitis media, skin and skin structure infections, and urinary tract infections. Amoxicillin is given with omeprazole in the treatment of Helicobacter pylori ( H. pylori ) infection. Amoxicillin is used in combination with vonoprazan and clarithromycin as co-packaged triple therapy or in combination with vonoprazan as co-packaged dual therapy to treat H. pylori infection in adults. Certolizumab pegol pharmacodynamics: As part of the mechanism of action and nature of the drug, certolizumab does not induce apoptosis in cultured lymphocytes and monocytes. However, as a piece of the inhibition of inflammation, certolizumab pegol inhibits lipopolysaccharide-induced production of IL-1 beta and it induces nonapoptotic cell death via signaling transmembrane TNF-alpha. In vitro studies with certolizumab pegol in human tissue did not show any unexpected binding at 3 mcg/ml nor at 10 mcg/ml. Due to the drug class, certolizumab pegol is not expected to present adverse effects on the major vital systems. In phase III clinical trials in psoriatic arthritis patients, certolizumab pegol was reported to generate improvements in skin disease, joint involvement, dactylitis, enthesitis and general life quality. The clinical effect of certolizumab was paired to a comparable safety profile to other TNF-alpha inhibitors. The clinical effectiveness of certolizumab pegol was mainly studied in six randomized controlled trials that compared its effect versus placebo. In a comparative study, the efficacy for certolizumab pegol registered ranged from 30-65% while in placebo ranged from 4-25%. However, in other additional trials, certolizumab was proven to present a similar clinical efficacy to other disease-modifying antirheumatic drugs in patients with inadequate response to TNF inhibitors. Amoxicillin pharmacodynamics: Amoxicillin competitively inhibit penicillin binding proteins, leading to upregulation of autolytic enzymes and inhibition of cell wall synthesis. Amoxicillin has a long duration of action as it is usually given twice daily. Amoxicillin has a wide therapeutic range as mild overdoses are not associated with significant toxicity. Patients should be counselled regarding the risk of anaphylaxis, Clostridium difficile infections, and bacterial resistance. The mechanism of action of Certolizumab pegol is that it Certolizumab targets the activation of TNF-alpha with high affinity (KD 90 pM and IC90 0. 004 mcg/ml) which inhibits the downstream inflammatory process. It acts by binding and neutralizing the soluble and membrane portions of TNF-alpha without inducing complement or antibody-dependent cytotoxicity due to the lack of the Fc region. The inhibition of TNF-alpha is achieved in a dose-dependent manner and it does not present activity against lymphotoxin alpha (TNF-beta). One additional feature od certolizumab pegol is that, due to the presence of the PEGylation, it is more significantly distributed into inflamed tissues when compared to other TNF-alpha inhibitors such as infliximab and adalimumab. The mechanism of action of Amoxicillin is that it Amoxicillin competitively inhibits penicillin-binding protein 1 and other high molecular weight penicillin binding proteins. Penicillin bind proteins are responsible for glycosyltransferase and transpeptidase reactions that lead to cross-linking of D-alanine and D-aspartic acid in bacterial cell walls. Without the action of penicillin binding proteins, bacteria upregulate autolytic enzymes and are unable to build and repair the cell wall, leading to bacteriocidal action. Certolizumab pegol absorption: After subcutaneous administration, the peak plasma concentration is reached between 54 and 171 hours with a bioavailability of 80%. Certolizumab presents a linear pharmacokinetic profile with a peak plasma concentration of 43-49 mcg/ml. Amoxicillin absorption: Amoxicillin is approximately 60% bioavailable. A 250mg dose of oral amoxicillin reaches a Cmax 3. 93±1. 13mg/L with a Tmax 1. 31±0. 33h and an AUC of 27. 29±4. 72mg*h/L. A 875mg dose of oral amoxicillin reaches a Cmax 11. 21±3. 42mg/L with a Tmax 1. 52±0. 40h and an AUC of 55. 04±12. 68mg*h/L. The volume of distribution of Certolizumab pegol is Certolizumab pegol volume of distribution is reported to be in the range of 4-8 L. It is known to have a very good distribution in the joints when compared to other TNF-alpha inhibitors. The volume of distribution of Amoxicillin is The central volume of distribution of amoxicillin is 27. 7L. Certolizumab pegol is Monoclonal antibodies are usually not required to have protein binding studies. bound to plasma proteins. Amoxicillin is Amoxicillin is 17% protein bound in serum. bound to plasma proteins. Certolizumab pegol metabolism: The presence of PEG group in certolizumab pegol delays the metabolism and elimination of this drug. However, once under metabolism, the PEG group gets cleaved from the parent compound and the antibody section is thought to be internalized cells and rescued from metabolism by recycling. Later, it is degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. On the other hand, the PEG section is processed normally by the action of the alcohol dehydrogenase to the formation of carboxylic acid. Amoxicillin metabolism: Incubation with human liver microsomes has lead to the detection of 7 metabolites. The M1 metabolite has undergone hydroxylation, M2 has undergone oxidative deamination, M3 to M5 have undergone oxidation of the aliphatic chain, M6 has undergone decarboxylation, and M7 has undergone glucuronidation. Certolizumab pegol is eliminated via As certolizumab is a monoclonal antibody, the elimination route is not widely studied. However, it is known that the elimination of the PEG moiety is dependent on the renal function which links it directly with a high portion of renal elimination. Amoxicillin is eliminated via 125mg to 1g doses of amoxicillin are 70-78% eliminated in the urine after 6 hours. The half-life of Certolizumab pegol is The circulatory half-life of certolizumab is of 14 days. The half-life of Amoxicillin is The half life of amoxicillin is 61. 3 minutes. The clearance of Certolizumab pegol is The clearance rate of certolizumab pegol ranged between 9-14 ml/h when administered intravenously. However, when administered subcutaneously, the clearance rate is estimated to range between 14-21 ml/h depending on the patient condition. The clearance of Amoxicillin is The mean clearance of amoxicillin is 21. 3L/h. Certolizumab pegol toxicity includes The oral ld50 observed in mice is determined to be of 300 mg/kg. To this date, there have not been reports of overdosage, however, in case of accidental overexposure close monitoring is recommended. Certolizumab pegol does not present mutagenic potential nor presents effects in fertility and reproductive performance. On the other hand, carcinogenicity studies have not been performed. Amoxicillin toxicity includes Patients experiencing an overdose may present with hematuria, oliguria, abdominal pain, acute renal failure, vomiting, diarrhea, rash, hyperactivity, and drowsiness. Treat overdose with symptomatic and supportive treatment, which may include emesis or hemodialysis. Brand names of Certolizumab pegol include Cimzia. Brand names of Amoxicillin include Amoxil, Augmentin, Clavulin, Moxatag, Omeclamox, Prevpac, Talicia, Voquezna 14 Day Dualpak 20;500, Voquezna 14 Day Triplepak 20;500;500. No synonyms are available for Certolizumab pegol. No synonyms are available for Amoxicillin. Amoxicilina Amoxicillin Amoxicilline Amoxicillinum Amoxycillin p-Hydroxyampicillin Certolizumab pegol summary: It is Certolizumab pegol is a tumor necrosis factor (TNF) blocker used to treat a variety of autoimmune and autoinflammatory conditions like Crohn's disease, rheumatoid arthritis, active psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, and plaque psoriasis. Amoxicillin summary: It is Amoxicillin is a penicillin derivative used for the treatment of infections caused by gram-positive bacteria, in particular streptococcal bacteria causing upper respiratory tract infections. Answer: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

Certolizumab pegol

Drug A is Risankizumab. Drug B is Methotrexate. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Methotrexate is combined with Risankizumab. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Risankizumab is indicated for Risankizumab is indicated to treat: moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. active psoriatic arthritis in adults. In Canada and Europe, it may be used alone or in combination with a conventional non-biologic disease-modifying antirheumatic drug (cDMARD) (e. g., methotrexate). moderately to severely active Crohn's disease in adults. In Canada, it is used in patients who have had an inadequate response, intolerance, or demonstrated dependence on corticosteroids; or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies. Methotrexate is indicated for Methotrexate oral solution is indicated for pediatric acute lymphoblastic leukemia and pediatric polyarticular juvenile idiopathic arthritis. Methotrexate injections for subcutaneous use are indicated for severe active rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and severe, recalcitrant, disabling psoriasis. It has also been approved by the EMA for the treatment of adult patients requiring systemic therapy for moderate-to-severe plaque psoriasis. Other formulations are indicated to treat gestational choriocarcinoma, chorioadenoma destruens, hydatiform mole, breast cancer, epidermoid cancer of the head and neck, advanced mycosis fungoides, lung cancer, and advanced non-Hodgkin's lymphoma. It is also used in the maintenance of acute lymphocytic leukemia. Methotrexate is also given before treatment with leucovorin to prolong relapse-free survival following surgical removal of a tumour in non-metastatic osteosarcoma. Risankizumab pharmacodynamics: Risankizumab works to suppress the inflammatory effects of interleukin (IL)-23. It inhibits the release of pro-inflammatory cytokines and chemokines. In vitro, risankizumab blocked IL-17 production; however, risankizumab does not actually bind to IL-17. Methotrexate pharmacodynamics: Methotrexate inhibits enzymes responsible for nucleotide synthesis which prevents cell division and leads to anti-inflammatory actions. It has a long duration of action and is generally given to patients once weekly. Methotrexate has a narrow therapeutic index. Do not take methotrexate daily. The mechanism of action of Risankizumab is that it Interleukin (IL)-23 is a pro-inflammatory cytokine implicated in various chronic inflammatory disorders, such as plaque psoriasis, psoriatic arthritis, and Crohn's disease. IL-23 binds to the IL-23 receptor to activate the IL-23/Th17 axis, which is responsible for mediating T cell-mediated immune responses and inflammation. The IL-23/Th17 axis triggers the differentiation of Th-17 and Th-22 cells and induces the release of inflammatory cytokines and chemokines such as IL-17. While the IL-23/Th17 axis serves a critical role in protection against pathogens, it is also involved in chronic, autoimmune, inflammatory disorders. IL-23 is made up of two subunits, p19 and p40: p19 is specific to IL-23 and p40 is present on both IL-12 and IL-23. Risankizumab binds to the p19 subunit of IL-23 with high affinity and neutralizes it, thereby preventing its interaction with the IL-23 receptor and activation of IL-23 signalling cascades. The mechanism of action of Methotrexate is that it Methotrexate enters tissues and is converted to a methotrexate polyglutamate by folylpolyglutamate. Methotrexate's mechanism of action is due to its inhibition of enzymes responsible for nucleotide synthesis including dihydrofolate reductase, thymidylate synthase, aminoimidazole caboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyltransferase. Inhibtion of nucleotide synthesis prevents cell division. In rheumatoid arthritis, methotrexate polyglutamates inhibit AICART more than methotrexate. This inhibition leads to accumulation of AICART ribonucleotide, which inhibits adenosine deaminase, leading to an accumulation of adenosine triphosphate and adenosine in the extracellular space, stimulating adenosine receptors, leading to anti-inflammatory action. Risankizumab absorption: Drug plasma concentrations increased dose-proportionally after subcutaneous administration of a single dose over the dose range from 18 mg to 360 mg and intravenous administration over a dose range from 200 mg to 1800 mg via a 3-hour infusion. In patients with plaque psoriasis who received a subcutaneous dose of 150 mg risankizumab, steady-state peak concentration (Cmax ) and trough concentration (C trough ) were 12 mcg/mL and 2 mcg/mL, respectively. In subjects with Crohn’s disease treated with 600 mg intravenous induction dose at Weeks 0, 4, and 8, followed by 180 mg or 360 mg subcutaneous maintenance dose at Week 12 and every 8 weeks thereafter, the median Cmax and Ctrough are estimated to be 156 mcg/mL and 38. 8 mcg/mL, respectively, during Weeks 8-12; and the steady state median Cmax and Ctrough are estimated to be 14. 0 mcg/mL and 4. 1 mcg/mL, respectively for 180 mg or 28. 0 mcg/mL and 8. 1 mcg/mL, respectively, for 360 mg, during Weeks 40-48. The absolute bioavailability of risankizumab was approximately 74 to 89% following subcutaneous injection. In healthy subjects, following administration of a single subcutaneous dose, Cmax was reached by 3 to 14 days. Methotrexate absorption: Methotrexate has a bioavailability of 64-90%, though this decreases at oral doses above 25mg due to saturation of the carrier mediated transport of methotrexate. Methotrexate has a Tmax of 1 to 2 hours. oral doses of 10-15µg reach serum levels of 0. 01-0. 1µM. The volume of distribution of Risankizumab is The estimated steady-state volume of distribution (inter-subject CV%) was 11. 2 L (34%) in subjects with plaque psoriasis, and 7. 68 L (64%) in subjects with Crohn’s disease. The volume of distribution of Methotrexate is The volume of distribution of methotrexate at steady state is approximately 1L/kg. Risankizumab is No information is available. bound to plasma proteins. Methotrexate is Methotrexate is 46. 5-54% bound to plasma proteins. bound to plasma proteins. Risankizumab metabolism: The metabolic pathway of risankizumab has not been fully characterized. As a humanized IgG1 monoclonal antibody, it is likely to be catabolized into small peptides and amino acids in the same way as endogenous IgG. Methotrexate metabolism: Methotrexate is metabolized by folylpolyglutamate synthase to methotrexate polyglutamate in the liver as well as in tissues. Gamma-glutamyl hydrolase hydrolyzes the glutamyl chains of methotrexate polyglutamates converting them back to methotrexate. A small amount of methotrexate is also converted to 7-hydroxymethotrexate. Risankizumab is eliminated via As an IgG1 monoclonal antibody, risankizumab is not expected to be filtered by glomerular filtration in the kidneys or to be excreted as an intact molecule in the urine. Methotrexate is eliminated via Methotrexate is >80% excreted as the unchanged drug and approximately 3% as the 7-hydroxylated metabolite. Methotrexate is primarily excreted in the urine with 8. 7-26% of an intravenous dose appearing in the bile. The half-life of Risankizumab is The terminal elimination half-life was approximately 28 days in patients with plaque psoriasis and 21 days in patients with Crohn’s disease. The half-life of Methotrexate is The half life of low dose methotrexate is 3 to 10 hours in adults. The half life for high dose methotrexate is 8 to 15 hours. Pediatric patients taking methotrexate for acute lymphoblastic anemia experience a terminal half life of 0. 7 to 5. 8 hours. Pediatric patients taking methotrexate for juvenile idiopathic arthritis experience a half life of 0. 9 to 2. 3 hours. The clearance of Risankizumab is The estimated systemic clearance (inter-subject CV%) was 0. 31 L/day (24%) in patients with plaque psoriasis and 0. 30 L/day (34%) in patients with Crohn’s disease. The clearance of Methotrexate is Methotrexate clearance varies widely between patients and decreases with increasing doses. Currently, predicting clearance of methotrexate is difficult and exceedingly high serum levels of methotrexate can still occur when all precautions are taken. Risankizumab toxicity includes The NOAEL was 50 mg/kg in monkeys following intravenous or subcutaneous administration. There is no information available regarding the overdose of risankizumab. Methotrexate toxicity includes The oral LD 50 in rats is 135mg/kg and in mice is 146mg/kg. Symptoms of overdose include hematologic and gastrointestinal reactions like leukopenia, thombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, and gastrointestinal bleeding. In the event of an overdose, patients should be treated with glucarpidase and not be given leucovorin for 2 hours before or after glucarpidase. Brand names of Risankizumab include Skyrizi 150 Mg Dose Pack. Brand names of Methotrexate include Metoject, Nordimet, Otrexup, Rasuvo, Reditrex, Trexall, Xatmep. No synonyms are available for Risankizumab. No synonyms are available for Methotrexate. Methotrexat Méthotrexate Methotrexate Methotrexatum Metotrexato Risankizumab summary: It is Risankizumab is an interleukin-23 antagonist used to treat plaque psoriasis, psoriatic arthritis, and Crohn's disease in adults. Methotrexate summary: It is Methotrexate is an antineoplastic agent used the treatment of a wide variety of cancers as well as severe psoriasis, severe rheumatoid arthritis, and juvenile rheumatoid arthritis. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Risankizumab

Drug A is Adefovir dipivoxil. Drug B is Ropivacaine. The severity of the interaction is minor. Adefovir dipivoxil may decrease the excretion rate of Ropivacaine which could result in a higher serum level. The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. Adefovir dipivoxil is indicated for Indicated for the treatment of chronic hepatitis B in adult patients with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease; this is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function. Ropivacaine is indicated for Ropivacaine is indicated in adult patients for the induction of regional or local anesthesia for surgery or acute pain management. Adefovir dipivoxil pharmacodynamics: Adefovir dipivoxil a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV). The concentration of adefovir that inhibited 50% of viral DNA synthesis (IC50) in vitro ranged from 0. 2 to 2. 5 μM in HBV transfected human hepatoma cell lines. The combination of adefovir with lamivudine showed additive anti-HBV activity. Ropivacaine pharmacodynamics: In contrast to most other local anesthetics, the presence of epinephrine does not affect the time of onset, duration of action, or the systemic absorption of ropivacaine. The mechanism of action of Adefovir dipivoxil is that it Adefovir dipivoxil is a prodrug of adefovir. Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0. 1 μM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1. 18 μM and 0. 97μM, respectively. The mechanism of action of Ropivacaine is that it Local anesthetics like ropivacaine block the generation and conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. Specifically, they block the sodium channel and decrease chances of depolarization and consequent action potentials. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Adefovir dipivoxil absorption: The approximate oral bioavailability of adefovir from HEPSERA is 59%. When a single oral 10 mg dose is given to chronic hepatitis B patients, the peak plasma concentration (Cmax) of adefovir was 18. 4 ± 6. 26 ng/mL. This occurred between 0. 58 - 4 hours post dose (Tmax). The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70. 0 ng∙h/mL. Food does not affect the exposure of adeforvir. Ropivacaine absorption: Ropivacaine pharmacokinetics are highly dependent on the dose, route of administration, and patient condition. Following epidural administration ropivacaine undergoes complete and biphasic absorption. The volume of distribution of Adefovir dipivoxil is 392 ± 75 mL/kg [Vd at steady state, intravenous administration of 1. 0 mg/kg/day]. 352 ± 9 mL/kg [Vd at steady state, intravenous administration of 3. 0 mg/kg/day] The volume of distribution of Ropivacaine is Following intravascular infusion, ropivacaine has a steady-state volume of distribution of 41 ± 7 liters. Ropivacaine is able to readily cross the placenta. Adefovir dipivoxil is ≤4% over the adefovir concentration range of 0. 1 to 25 μg/mL bound to plasma proteins. Ropivacaine is Ropivacaine is 94% protein-bound in plasma, primarily to α1-acid glycoprotein. bound to plasma proteins. Adefovir dipivoxil metabolism: Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. 45% of the dose is recovered as adefovir in the urine over 24 hours at steady state following 10 mg oral doses. Adefovir is not a substrate of the cytochrome P450 enzymes. Ropivacaine metabolism: Ropivacaine undergoes extensive metabolism, primarily via CYP1A2-mediated aromatic hydroxylation to 3-OH-ropivacaine. The main metabolites excreted in the urine are the N-dealkylated metabolite (PPX) and 3-OH-ropivacaine. Other identified metabolites include 4-OH-ropivacaine, the 3-hydroxy-N-dealkylated (3-OH-PPX) and 4-hydroxy-N-dealkylated (4-OH-PPX) metabolites, and 2-hydroxy-methyl-ropivacaine (which has been identified but not quantified). Unbound PPX, 3-hydroxy-, and 4-hydroxy-ropivacaine have demonstrated pharmacological activity in animal models less than that of ropivacaine. Adefovir dipivoxil is eliminated via Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion. Ropivacaine is eliminated via Following intravenous administration, 86% of the administered dose of ropivacaine is excreted in the urine, 1% of which comprises unchanged parent drug. The half-life of Adefovir dipivoxil is Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7. 48 ± 1. 65 hours. The half-life of Ropivacaine is The mean terminal half-life of ropivacaine is 1. 8 ± 0. 7 hours after intravascular administration and 4. 2 ± 1 hour after epidural administration. The clearance of Adefovir dipivoxil is 469 ± 99. 0 mL/min [Patients with Unimpaired renal Function receiving a 10 mg single dose]. 356 ± 85. 6 mL/min [Patients with mild renal impairement receiving a 10 mg single dose] 237 ± 118 mL/min [Patients with moderate renal impairement receiving a 10 mg single dose] 91. 7 ± 51. 3 mL/min [Patients with severe renal impairement receiving a 10 mg single dose] The clearance of Ropivacaine is Following intravenous administration, ropivacaine has a mean plasma clearance of 387 ± 107 mL/min, an unbound plasma clearance of 7. 2 ± 1. 6 L/min, and a renal clearance of 1 mL/min. Adefovir dipivoxil toxicity includes Renal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3–10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day. Ropivacaine toxicity includes High systemic doses of ropivacaine can result in central nervous system (CNS) and cardiovascular effects, with the CNS effects usually occurring at lower blood plasma concentrations and additional cardiovascular effects occurring at higher concentrations (although cardiovascular collapse may occur at lower concentrations). CNS effects include CNS excitation involving nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, and seizures. CNS depressant effects may follow, associated with drowsiness, loss of consciousness, respiratory depression and apnea. Cardiovascular events may be caused by hypoxemia secondary to respiratory depression and include hypotension, bradycardia, arrhythmias, and/or cardiac arrest. Brand names of Adefovir dipivoxil include Hepsera. Brand names of Ropivacaine include Naropin. No synonyms are available for Adefovir dipivoxil. Adefovir pivoxil bis-POM PMEA No synonyms are available for Ropivacaine. Ropivacaina Ropivacaine Ropivacainum Adefovir dipivoxil summary: It is Adefovir dipivoxil is a nucleotide analog used to treat chronic hepatitis B. Ropivacaine summary: It is Ropivacaine is an amide-type local anesthetic used for local or regional anesthesia during surgery and for short-term management of acute pain. Answer: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects.

Adefovir dipivoxil

Drug A is Brentuximab vedotin. Drug B is Polatuzumab vedotin. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Polatuzumab vedotin. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Brentuximab vedotin is indicated for Brentuximab vedotin is indicated in adult patients for the treatment of previously untreated stage III or IV classical Hodgkin's lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine. It is also indicated for the treatment of cHL post-autologous hematopoietic stem cell transplantation (auto-HSCT) in patients at high risk of relapse or progression. Finally, it may be used in the treatment of adult patients with cHL who have previously failed either auto-HSCT or at least two prior multi-agent chemotherapy regimens if they are not candidates for auto-HSCT. Brentuximab vedotin is additionally indicated in the treatment of previously untreated systemic anaplastic large cell lymphoma (sALCL), or other CD30-expressing peripheral T-cell lymphomas (PTCL), in combination with cyclophosphamide, doxorubicin, and prednisone. It may also be used as monotherapy in sALCL after therapeutic failure of a least one prior multi-agent chemotherapy regimen. Brentuximab vedotin is also indicated in the treatment of primary cutaneous large anaplastic large cell lymphoma, or CD30-expressing mycosis fungoides, who have received prior systemic therapy. Polatuzumab vedotin is indicated for Polatuzumab vedotin is used in combination with bendamustine and rituximab to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, after at least two prior therapies. In Canada, this indication is approved for patients who are not eligible for autologous stem cell transplant and have received at least one prior therapy. Polatuzumab vedotin is also used in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) to treat adult patients with previously untreated large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), high-grade B-cell lymphoma, Epstein-Barr virus-positive (EBV+) DLBCL NOS, and T-cell/histiocyte rich LBCL. Brentuximab vedotin pharmacodynamics: Brentuximab vedotin causes apoptosis of tumor cells by preventing cell cycle progression of the G2 to M phase through disruption of the cytosolic microtuble network, thus preventing tumor growth and proliferation. Hodgkin lymphoma (HL) is characterized by malignant Reed-Sternberg cells which express CD30, a marker of large cell lymphoma. Until March 2018, USA National Comprehensive Cancer Network guidelines for patients with advanced HL (stage III/IV disease) recommend treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), or escalated bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) as first-line regimens. ABVD appears to be as effective, with fewer side effects, as escalated BEACOPP. Escalated BEACOPP leads to a greater progression-free survival but no difference in overall survival. Recent progress in technology has enabled a new shift to cancer therapy targeting specific molecules. Brentuximab vedotin, a CD30-directed antibody conjugate, selectively targets malignant HL cells. The effect of Brentuximab vedotin (1. 8 mg/kg) on the QTc interval was studied in an open-label, single-group study in 46 patients diagnosed with CD30-expressing hematologic malignancies. Ingestion of brentuximab vedotin did not prolong the mean cardiac QTc interval >10 ms from baseline levels. Smaller increases in the mean QTc interval (<10 ms) cannot be ruled out because this study did not include a placebo arm and a positive control arm. Polatuzumab vedotin pharmacodynamics: Polatuzumab vedotin is an anti-cancer agent that works to cause apoptosis in malignant B cells. In vitro, it exerted cytotoxic effects on most diffuse large B-cell lymphoma (DLBCL) cell lines: this effect was consistent across cell lines, regardless of the cell-of-origin subtypes and whether they harboured mutations in the CD79B gene or not. In mouse xenograft models, polatuzumab vedotin caused apoptosis and reduced proliferation of mature CD79b+ B-cell NHL cell lines. Polatuzumab vedotin can cause immunosuppression, including neutropenia and thrombocytopenia. The mechanism of action of Brentuximab vedotin is that it Brentuximab vedotin is composed of 3 parts: a chimeric human-murine IgG1 that selectively targets CD30, monomethyl auristatin E (MMAE), which is a microtubule-disrupting agent, and a protease-susceptible linker that links the antibody and MMAE. The IgG1 antibody enables Brentuximab vedotin to target tumor cells expressing CD30 on their surface. Following this Brentuximab vedotin enters the cell. Once inside, the linker is cleaved releasing MMAE which binds disrupts the microtubule network. The antibody component of this drug is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule-disrupting particle. MMAE is covalently attached to the antibody by a linker. Data suggest that the anticancer activity of Adcertris is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the subsequent release of MMAE by proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptotis of the malignant cells. The mechanism of action of Polatuzumab vedotin is that it Polatuzumab vedotin is an antibody-drug conjugate consisting of a CD79b-directed antibody, a microtubule-disrupting agent called monomethyl auristatin E (MMAE), and a cleavable linker that holds the components together. CD79 is a heterodimer composed of CD79a and CD79b. Responsible for signal transduction, CD79 forms a complex with the B cell receptor (BCR) and is almost exclusively expressed on B cells, including malignant B cells. Most importantly, CD79b gained increasing attention as a promising therapeutic target as it plays an essential role in BCR expression, transport, and functions such as B cell proliferation and differentiation. Once the antibody component binds to CD79b, polatuzumab vedotin is internalized, and lysosomal proteases cleave the linker to release MMAE in the cell. MMAE is a microtubule-disrupting anti-mitotic agent that exerts cytotoxic effects against malignant B cells. It binds to microtubules, inhibits mitosis by interfering with tubulin and tubulin polymerization, and induces apoptosis in dividing B cells. Brentuximab vedotin absorption: Steady-state of the ADC is achieved within 21 days with every 3-week dosing of Adcetris. Minimal to no accumulation of ADC is observed with multiple doses at the every 3-week schedule. The time to maximum concentration for MMAE ranges from approximately 1 to 3 days. Similar to the ADC, steady-state of MMAE is achieved within 21 days with every 3-week dosing of Adcetris. MMAE exposures decrease with continued administration of Adcetris with about 50% to 80% of the exposure of the first dose being observed at future doses. The AUC of MMAE was measured to be approximately 2. 2-fold higher in patients with hepatic impairment in comparison with patients with normal hepatic function. Polatuzumab vedotin absorption: After the first polatuzumab vedotin dose of 1. 8 mg/kg, the mean (± SD) Cmax of antibody-conjugated MMAE and unconjugated MMAE were 803 (± 233) ng/mL and 6. 82 (± 4. 73) ng/mL, respectively. The mean AUC inf of antibody-conjugated MMAE and unconjugated MMAE were 1860 (± 966) day x ng/mL and 52. 3 (± 18. 0) day x ng/mL, respectively. The volume of distribution of Brentuximab vedotin is MMAE is unlikely to displace or to be displaced by highly protein-bound drugs. In vitro studies show that MMAE is a substrate of P-gp and was not a potent inhibitor of P-gp. The volume of distribution of Polatuzumab vedotin is The estimated central volume of distribution of polatuzumab vedotin based on population PK analysis is 3. 15 L. Brentuximab vedotin is In vitro, the binding of MMAE to human plasma proteins is in the range of 68–82%. bound to plasma proteins. Polatuzumab vedotin is MMAE is 71% to 77% bound to plasma proteins. Its blood-to-plasma ratio is 0. 79 to 0. 98, in vitro. bound to plasma proteins. Brentuximab vedotin metabolism: Data in both animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes. Polatuzumab vedotin metabolism: Polatuzumab vedotin is expected to undergo catabolism into small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. MMAE is metabolized by CYP3A4/5. Brentuximab vedotin is eliminated via This drug appears follow metabolite kinetics, with the elimination of appearing to be limited by its rate of release from the antibody-drug conjugate (ADC). An excretion study was done in patients receiving a dose of 1. 8 mg/kg of Adcetris. About 24% of the total MMAE ingested as part of the ADC during an ADCETRIS infusion was recovered in both urine and feces over a 7-day time frame. Of the recovered MMAE, approximately 72% was found in the feces and the majority of the excreted MMAE was excreted as unchanged drug. Polatuzumab vedotin is eliminated via Polatuzumab vedotin is predominantly excreted in feces, as well as in urine to some extent. The half-life of Brentuximab vedotin is The terminal half-life is approximately 4-6 days. The half-life of Polatuzumab vedotin is The terminal half-life of polatuzumab vedotin is approximately 12 days (95% CI: 8. 1 to 19. 5 days) at Cycle 6. The terminal half-life of unconjugated MMAE is approximately four days after the first dose of polatuzumab vedotin. The clearance of Brentuximab vedotin is The liver is the primary route of clearance for MMAE. The pharmacokinetics and safety of Brentuximab vedotin and MMAE were examined after the administration of 1. 2 mg/kg of Adcetris to patients with mild, moderate, and severe hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ≥Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function. It is recommended to avoid use in patients with severe renal impairment (CrCl <30mL/min). The clearance of Polatuzumab vedotin is The predicted clearance of polatuzumab vedotin is 0. 9 L/day. Brentuximab vedotin toxicity includes The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML) follows infection by the JC virus (which is not related to Creutzfeldt-Jakob disease). Symptoms of this condition begin insidiously and usually worsen progressively. The symptoms vary depending on which region of the brain is infected. In about two out of three patients, mental function deteriorates rapidly, leading to dementia. Speaking and walking may become increasingly difficult. Vision may be impaired, and total blindness may occur. Rarely, headaches and seizures can occur, mainly in immunocompromised patients. The most serious sequela of this condition is death. Common adverse effects of Adcetris may include: neutropenia, anemia, peripheral neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and fever. In one trial, neutropenia occurred in 91 percent of patients treated with Adcetris plus chemotherapy, which was associated with a 19 percent rate of febrile neutropenia (neutropenia and fever). Preventive treatment with G-CSF, a growth factor for the bone marrow to produce white blood cells, is recommended with Adcetris plus chemotherapy for the first-line treatment of Stage III or IV cHL. Adcetris has a boxed warning that emphasizes the risk of John Cunningham virus infection leading to progressive multifocal leukoencephalopathy, or PML, a rare but serious brain infection that may be lethal. Serious risks of Adcetris include peripheral neuropathy; severe allergic (anaphylaxis) or infusion-site reactions; damage to the blood, lungs and liver (hematologic, pulmonary and hepato-toxicities); severe/opportunistic infections; metabolic abnormalities (tumor lysis syndrome); dermatologic reactions and gastrointestinal complications. Adcetris may cause harm to the fetus and newborn baby; women should be warned of the potential risk to the fetus and to use effective contraception, and to avoid breastfeeding while taking Adcetris. MMAE was found to be genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting drug. Fertility studies with Brentuximab vedotin or MMAE have not been conducted. Despite this, results of repeat-dose toxicity studies in rats suggest the potential for Brentuximab vedotin to have a negative effect on male reproductive function and fertility. In a 4-week repeated-dose toxicity study in rats with weekly dosing at 0. 5, 5 or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed. Effects in animals were seen mostly at 5 and 10 mg/kg doses of brentuximab vedotin. These dosages are approximately 3 and 6-fold the human recommended dose of 1. 8 mg/kg, respectively, based on individual body weight. Polatuzumab vedotin toxicity includes Data regarding overdoses and LD 50 are not readily available. Brand names of Brentuximab vedotin include Adcetris. Brand names of Polatuzumab vedotin include Polivy. No synonyms are available for Brentuximab vedotin. No synonyms are available for Polatuzumab vedotin. Brentuximab vedotin summary: It is Brentuximab vedotin is a CD30-directed antibody-drug conjugate used to treat various types of lymphoma. Polatuzumab vedotin summary: It is Polatuzumab vedotin is a CD79b antibody conjugate indicated to treat different types of large B-cell lymphoma. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Brentuximab vedotin

Drug A is Acarbose. Drug B is Insulin aspart. The severity of the interaction is moderate. The risk or severity of hypoglycemia can be increased when Acarbose is combined with Insulin aspart. The use of insulin and other antidiabetic agents concomitantly can have an additive effect in lowering blood glucose, thus increasing the risk of hypoglycemia. Acarbose is indicated for Acarbose is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Insulin aspart is indicated for Insulin aspart is indicated to improve glycemic control in adults and children with diabetes mellitus. Acarbose pharmacodynamics: Acarbose is a complex oligosaccharide that competitively inhibits the ability of brush-border alpha-glucosidase enzymes to break down ingested carbohydrates into absorbable monosaccharides, reducing carbohydrate absorption and subsequent postprandial insulin levels. Acarbose requires the co-administration of carbohydrates in order to exert its therapeutic effect, and as such should be taken with the first bite of a meal three times daily. Given its mechanism of action, acarbose in isolation poses little risk of contributing to hypoglycemia - this risk is more pronounced, however, when acarbose is used in conjunction with other antidiabetic therapies (e. g. sulfonylureas, insulin). Patients maintained on acarbose in addition to other antidiabetic agents should be aware of the symptoms and risks of hypoglycemia and how to treat hypoglycemic episodes. There have been rare post-marketing reports of the development of pneumatosis cystoides intestinalis following treatment with alpha-glucosidase inhibitors - patients experiencing significant diarrhea/constipation, mucus discharge, and/or rectal bleeding should be investigated and, if pneumatosis cystoides intestinalis is suspected, should discontinue therapy. Insulin aspart pharmacodynamics: Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Postprandial insulin spikes are responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e. g. protein synthesis, cell division, DNA synthesis). Insulin aspart is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin aspart is 10-15 minutes. Its activity peaks 60-90 minutes following subcutaneous injection and its duration of action is 4-5 hours. The mechanism of action of Acarbose is that it Alpha-glucosidase enzymes are located in the brush-border of the intestinal mucosa and serve to metabolize oligo-, tri-, and disaccharides (e. g. sucrose) into smaller monosaccharides (e. g. glucose, fructose) which are more readily absorbed. These work in conjunction with pancreatic alpha-amylase, an enzyme found in the intestinal lumen that hydrolyzes complex starches to oligosaccharides. Acarbose is a complex oligosaccharide that competitively and reversibly inhibits both pancreatic alpha-amylase and membrane-bound alpha-glucosidases - of the alpha-glucosidases, inhibitory potency appears to follow a rank order of glucoamylase > sucrase > maltase > isomaltase. By preventing the metabolism and subsequent absorption of dietary carbohydrates, acarbose reduces postprandial blood glucose and insulin levels. The mechanism of action of Insulin aspart is that it Insulin aspart binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Substitution of the proline residue at B28 with aspartic acid reduces the tendency to form hexamers and results in a faster rate of absorption and onset of action and shorter duration of action. Acarbose absorption: The oral bioavailability of acarbose is extremely minimal, with less than 1-2% of orally administered parent drug reaching the systemic circulation. Despite this, approximately 35% of the total radioactivity from a radiolabeled and orally administered dose of acarbose reaches the systemic circulation, with peak plasma radioactivity occurring 14-24 hours after dosing - this delay is likely reflective of metabolite absorption rather than absorption of the parent drug. As acarbose is intended to work within the gut, its minimal degree of oral bioavailability is therapeutically desirable. Insulin aspart absorption: In studies of healthy volunteers and patients with type 1 diabetes, the median time to maximum concentration of insulin aspart in these trials was 40 to 50 minutes versus 80 to 120 minutes, for regular human insulin respectively. Compared to human insulin, insulin aspart has a faster absorption, a faster onset of action, and a shorter duration of action than regular human insulin after subcutaneous injection. It takes 40 - 50 minutes to reach maximum concentration. When a dose of 0. 15 U/kg body weight was injected in type 1 diabetes patients, the mean maximum concentration (Cmax) was 82 mU/L. The site of injection has no impact on extent or speed of absorption. No volume of distribution information is available for Acarbose. No volume of distribution information is available for Insulin aspart. Acarbose is As only 1-2% of an orally administered dose is absorbed into the circulation, acarbose is unlikely to be subject to clinically relevant protein binding. bound to plasma proteins. Insulin aspart is Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin. bound to plasma proteins. Acarbose metabolism: Acarbose is extensively metabolized within the gastrointestinal tract, primarily by intestinal bacteria and to a lesser extent by digestive enzymes, into at least 13 identified metabolites. Approximately 1/3 of these metabolites are absorbed into the circulation where they are subsequently renally excreted. The major metabolites appear to be methyl, sulfate, and glucuronide conjugates of 4-methylpyrogallol. Only one metabolite - resulting from the cleavage of a glucose molecule from acarbose - has been identified as having alpha-glucosidase inhibitory activity. No metabolism information is available for Insulin aspart. Acarbose is eliminated via Roughly half of an orally administered dose is excreted in the feces within 96 hours of administration. What little drug material is absorbed into the systemic circulation (approximately 34% of an orally administered dose) is excreted primarily by the kidneys, suggesting renal excretion would be a significant route of elimination if the parent drug was more readily absorbed - this is further supported by data in which approximately 89% of an intravenously administered dose of acarbose was excreted in the urine as active drug (in comparison to <2% following oral administration) within 48 hours. Insulin aspart is eliminated via No route of elimination available. The half-life of Acarbose is In healthy volunteers, the plasma elimination half-life of acarbose is approximately 2 hours. The half-life of Insulin aspart is Elimination half-life was found to be 81 minutes (following subcutaneous administration in healthy subjects). No clearance information is available for Acarbose. The clearance of Insulin aspart is 1. 2 L/h/kg. Acarbose toxicity includes The symptoms of acarbose overdose are likely to be consistent with its adverse effect profile and may therefore include significant gastrointestinal (GI) symptoms (flatulence, distension, etc), although an overdose on an empty stomach (i. e. when not co-administered with food) is less likely to result in these GI symptoms. In the event of an overdose, patients should be instructed to avoid carbohydrate-containing foods for 4-6 hours following administration as these can precipitate the aforementioned GI symptoms. Insulin aspart toxicity includes Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. Brand names of Acarbose include Precose. Brand names of Insulin aspart include Fiasp, Novolog, Novolog Mix, Novomix, Novorapid, Novorapid Penfill, Ryzodeg. No synonyms are available for Acarbose. No synonyms are available for Insulin aspart. Acarbose summary: It is Acarbose is an alpha-glucosidase inhibitor used in adjunctly with diet and exercise for the management of glycemic control in patients with type 2 diabetes mellitus. Insulin aspart summary: It is Insulin aspart is a rapid-acting form of insulin used for glycemic control in type 1 and type 2 diabetes mellitus. Answer: The use of insulin and other antidiabetic agents concomitantly can have an additive effect in lowering blood glucose, thus increasing the risk of hypoglycemia.

Acarbose

Drug A is Adefovir dipivoxil. Drug B is Pralidoxime. The severity of the interaction is minor. Adefovir dipivoxil may decrease the excretion rate of Pralidoxime which could result in a higher serum level. The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. Adefovir dipivoxil is indicated for Indicated for the treatment of chronic hepatitis B in adult patients with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease; this is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function. Pralidoxime is indicated for the treatment of poisoning due to those pesticides and chemicals of the organophosphate class which have anticholinesterase activity and in the control of overdosage by anticholinesterase drugs used in the treatment of myasthenia gravis. Adefovir dipivoxil pharmacodynamics: Adefovir dipivoxil a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV). The concentration of adefovir that inhibited 50% of viral DNA synthesis (IC50) in vitro ranged from 0. 2 to 2. 5 μM in HBV transfected human hepatoma cell lines. The combination of adefovir with lamivudine showed additive anti-HBV activity. Pralidoxime pharmacodynamics: Pralidoxime is to reactivate cholinesterase (mainly outside of the central nervous system) which has been inactivated by phosphorylation due to an organophosphate pesticide or related compound. The destruction of accumulated acetylcholine can then proceed, and neuromuscular junctions will again function normally. Pralidoxime also slows the process of "aging" of phosphorylated cholinesterase to a nonreactivatable form, and detoxifies certain organophosphates by direct chemical reaction. The drug has its most critical effect in relieving paralysis of the muscles of respiration. Because pralidoxime is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Pralidoxime relieves muscarinic signs and symptoms, salivation, bronchospasm, etc., but this action is relatively unimportant since atropine is adequate for this purpose. The mechanism of action of Adefovir dipivoxil is that it Adefovir dipivoxil is a prodrug of adefovir. Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0. 1 μM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1. 18 μM and 0. 97μM, respectively. The mechanism of action of Pralidoxime is that it Pralidoxime is an antidote to organophosphate pesticides and chemicals. Organophosphates bind to the esteratic site of acetylcholinesterase, which results initially in reversible inactivation of the enzyme. Acetylcholinesterase inhibition causes acetylcholine to accumulate in synapses, producing continuous stimulation of cholinergic fibers throughout the nervous systems. If given within 24 hours after organophosphate exposure, pralidoxime reactivates the acetylcholinesterase by cleaving the phosphate-ester bond formed between the organophosphate and acetylcholinesterase. Adefovir dipivoxil absorption: The approximate oral bioavailability of adefovir from HEPSERA is 59%. When a single oral 10 mg dose is given to chronic hepatitis B patients, the peak plasma concentration (Cmax) of adefovir was 18. 4 ± 6. 26 ng/mL. This occurred between 0. 58 - 4 hours post dose (Tmax). The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70. 0 ng∙h/mL. Food does not affect the exposure of adeforvir. No absorption information is available for Pralidoxime. The volume of distribution of Adefovir dipivoxil is 392 ± 75 mL/kg [Vd at steady state, intravenous administration of 1. 0 mg/kg/day]. 352 ± 9 mL/kg [Vd at steady state, intravenous administration of 3. 0 mg/kg/day] No volume of distribution information is available for Pralidoxime. Adefovir dipivoxil is ≤4% over the adefovir concentration range of 0. 1 to 25 μg/mL bound to plasma proteins. Pralidoxime is No binding to plasma proteins bound to plasma proteins. Adefovir dipivoxil metabolism: Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. 45% of the dose is recovered as adefovir in the urine over 24 hours at steady state following 10 mg oral doses. Adefovir is not a substrate of the cytochrome P450 enzymes. Pralidoxime metabolism: Hepatic. Adefovir dipivoxil is eliminated via Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion. Pralidoxime is eliminated via The drug is rapidly excreted in the urine partly unchanged, and partly as a metabolite produced by the liver. The half-life of Adefovir dipivoxil is Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7. 48 ± 1. 65 hours. The half-life of Pralidoxime is 74-77 minutes. The clearance of Adefovir dipivoxil is 469 ± 99. 0 mL/min [Patients with Unimpaired renal Function receiving a 10 mg single dose]. 356 ± 85. 6 mL/min [Patients with mild renal impairement receiving a 10 mg single dose] 237 ± 118 mL/min [Patients with moderate renal impairement receiving a 10 mg single dose] 91. 7 ± 51. 3 mL/min [Patients with severe renal impairement receiving a 10 mg single dose] No clearance information is available for Pralidoxime. Adefovir dipivoxil toxicity includes Renal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3–10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day. No toxicity information is available for Pralidoxime. Brand names of Adefovir dipivoxil include Hepsera. Brand names of Pralidoxime include Atnaa, Duodote, Protopam. No synonyms are available for Adefovir dipivoxil. Adefovir pivoxil bis-POM PMEA No synonyms are available for Pralidoxime. Adefovir dipivoxil summary: It is Adefovir dipivoxil is a nucleotide analog used to treat chronic hepatitis B. Pralidoxime summary: It is Pralidoxime is a cholinesterase reactivator used to treat organophosphate poisoning. Answer: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects.

Adefovir dipivoxil

Drug A is Aceclofenac. Drug B is Dexpanthenol. The severity of the interaction is minor. Aceclofenac may decrease the excretion rate of Dexpanthenol which could result in a higher serum level. The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. Aceclofenac is indicated for Aceclofenac is indicated for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Dexpanthenol is indicated for Injection: Prophylactic use immediately after major abdominal surgery to minimize the possibility of paralytic ileus. Intestinal atony causing abdominal distention; postoperative or postpartum retention of flatus, or postoperative delay in resumption of intestinal motility; paralytic ileus. Topical: This medication is used as a moisturizer to treat or prevent dry, rough, scaly, itchy skin and minor skin irritations (e. g., diaper rash, skin burns from radiation therapy). Aceclofenac pharmacodynamics: Aceclofenac is a NSAID that inhibits both isoforms of COX enzyme, a key enzyme involved in the inflammatory cascade. COX-1 enzyme is a constitutive enzyme involved in prostacyclin production and protective functions of gastric mucosa whereas COX-2 is an inducible enzyme involved in the production of inflammatory mediators in response to inflammatory stimuli. Aceclofenac displays more selectivity towards COX-2 (IC50 of 0. 77uM) than COX-1 (IC50 of >100uM), which promotes its gastric tolerance compared to other NSAIDs. The primary metabolite, 4'-hydroxyaceclofenac, also minimally inhibits COX-2 with IC50 value of 36uM. Although the mode of action of aceclofenac is thought to mainly arise from the inhibition of synthesis of prostaglandins (PGE2), aceclofenac also inhibits the production of inflammatory cytokines, interleukins (IL-1β, IL-6), and tumor necrosis factors (TNF). It is also reported that aceclofenac also affects the cell adhesion molecules from neutrophils. Aceclofenac also targets the synthesis of glycosaminoglycan and mediates chrondroprotective effects. Dexpanthenol pharmacodynamics: Pantothenic acid is a precursor of coenzyme A, which serves as a cofactor for a variety of enzyme-catalyzed reactions involving transfer of acetyl groups. The final step in the synthesis of acetylcholine consists of the choline acetylase transfer of acetyl group from acetylcoenzyme A to choline. Acetylcholine is the neurohumoral transmitter in the parasympathetic system and as such maintains the normal functions of the intestine. Decrease in acetylcholine content would result in decreased peristalsis and in extreme cases adynamic ileus. The mechanism of action of Aceclofenac is that it Through COX-2 inhibition, aceclofenac downregulates the production of various inflammatory mediators including prostaglandin E2 (PGE2), IL-1β, and TNF from the arachidonic acid (AA) pathway. Inhibition of IL-6 is thought to be mediated by diclofenac converted from aceclofenac. Suppressed action of inflammatory cytokines decreases the production of reactive oxygen species. Aceclofenac is shown to decreased production of nitrous oxide in human articular chondrocytes. In addition, aceclofenac interferes with neutrophil adhesion to endothelium by decreasing the expression of L-selectin (CD62L), which is a cell adhesion molecule expressed on lymphocytes. Aceclofenac is proposed to stimulate the synthesis of glycosaminoglycan in human osteoarthritic cartilage which may be mediated through its inhibitory action on IL-1 production and activity. The chrondroprotective effects are generated by 4'-hydroxyaceclofenac which suppresses IL-1 mediated production of promatrix metalloproteinase-1 and metalloproteinase-3 and interferes with the release of proteoglycan from chrondrocytes. The mechanism of action of Dexpanthenol is that it Dexpanthenol is an alcohol derivative of pantothenic acid, a component of the B complex vitamins and an essential component of a normally functioning epithelium. Dexpanthenol is enzymatically cleaved to form pantothenic acid, which is an essential component of Coenzyme A, which acts as a cofactor in many enzymatic reactions that are important for protein metabolism in the epithelium. Dermatological effects of the topical use of dexpanthenol include increased fibroblast proliferation and accelerated re-epithelialization in wound healing. Furthermore, it acts as a topical protectant, moisturizer, and has demonstrated anti-inflammatory properties. Aceclofenac absorption: Aceclofenac is rapidly and completely absorbed from the gastrointestinal tract and circulates mainly as unchanged drug following oral administration. Peak plasma concentrations are reached around 1. 25 to 3 hours post-ingestion, and the drug penetrates into the synovial fluid where the concentration may reach up to 60% of that in the plasma. There is no accumulation in regular dosing, with similar maximum plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax) after single and multiple doses. Dexpanthenol absorption: Dexpanthenol is soluble in water and alcohol, although insoluble in fats and oil based substances. With the appropriate vehicle, Dexpanthenol is easily penetrated into the skin. Rate of penetration and absorption is reduced when Dexpanthenol is administered as an oil/water formula. The volume of distribution of Aceclofenac is The volume of distribution is approximately 25 L. The volume of distribution of Dexpanthenol is Dexpanthenol is readily converted to pantothenic acid which is widely distributed into body tissues, mainly as coenzyme A. Highest concentrations are found in the liver, adrenal glands, heart, and kidneys. Aceclofenac is It is reported to be highly protein-bound (>99%). bound to plasma proteins. Dexpanthenol is Plasma protein binding have not been reported. bound to plasma proteins. Aceclofenac metabolism: 4'-hydroxyaceclofenac is the main metabolite detected in plasma however other minor metabolites include diclofenac, 5-hydroxyaceclofenac, 5-hydroxydiclofenac, and 4'-hydroxydiclofenac. It is probable that the metabolism of aceclofenac is mediated by CYP2C9. Dexpanthenol metabolism: Dexpanthenol is readily converted to pantothenic acid which is widely distributed into body tissues, mainly as coenzyme A. Aceclofenac is eliminated via The main route of elimination is via the urine where the elimination accounts for 70-80% of clearance of the drug. Approximately two thirds of the administered dose is excreted via the urine, mainly as glucuronidated and hydroxylated forms of aceclofenac. About 20% of the dose is excreted into feces. Dexpanthenol is eliminated via Milk of nursing mothers receiving a normal diet contains about 2 ug of pantothenic acid per mL. About 70% of an oral dose of pantothenic acid is excreted unchanged in urine and about 30% in feces. The half-life of Aceclofenac is The mean plasma elimination half-life is approximately 4 hours. The half-life of Dexpanthenol is Half life have not been reported. The clearance of Aceclofenac is The mean clearance rate is approximately 5 L/h. No clearance information is available for Dexpanthenol. Aceclofenac toxicity includes Some common adverse effects include gastro-intestinal disorders (dyspepsia, abdominal pain, nausea), rash, ruber, urticaria, symptoms of enuresis, headache, dizziness, and drowsiness. Oral LD50 value in rats is 130 mg/kg. Dexpanthenol toxicity includes Mouse LD50: 9gm/kg (Intraperitoneal). Mouse is LD50 7gm/kg (Intravenous). Mouse is LD50 15gm/kg (Oral). Rabbit LD50 4gm/kg (Oral) Brand names of Aceclofenac include No brand names available. Brand names of Dexpanthenol include Fortaplex, Infuvite, Infuvite Pediatric, Mvi Pediatric, Neo-bex. No synonyms are available for Aceclofenac. Acéclofénac Aceclofenac betadex Aceclofenaco Aceclofenacum No synonyms are available for Dexpanthenol. Bepanthene Bepantol D-panthenol D-panthenol 50 D-Pantothenol D-Pantothenyl alcohol Dexpantenol Dexpanthenol Dexpanthenolum Pantol Pantothenyl alcohol Provitamin B Aceclofenac summary: It is No summary available. Dexpanthenol summary: It is Dexpanthenol is an alcoholic analogue of D-pantothenic acid that is used as a supplement or application to support a healthy epithelium and is also used to prevent vitamin deficiency in patients receiving total parenteral nutrition (TPN). Answer: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects.

Aceclofenac

Drug A is Peginterferon alfa-2b. Drug B is Dacarbazine. The severity of the interaction is minor. The serum concentration of Dacarbazine can be increased when it is combined with Peginterferon alfa-2b. Peginterferon alfa 2b is a limited inhibitor of CYP1A2. Peginterferon alfa-2b is indicated for Peginterferon alfa-2b is indicated for the treatment of HCV in combination with Ribavirin and a NS3/4A protease inhibitor for genotype 1 or without a NS3/4A protease inhibitor for genotypes 2-6. May be used as a monotherapy in patients with contraindications to or significant intolerance to other anti-viral therapies. It is also indicated for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy. Dacarbazine is indicated for the treatment of metastatic malignant melanoma. In addition, dacarbazine is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other antineoplastic agents. Peginterferon alfa-2b pharmacodynamics: Peginterferon alfa-2b inhibits viral replication in infected cells, suppresses cell proliferation, induces apoptosis, and exerts an anti-angiogenic effect. Exerts immunomodulatory effects such as enhancement of the phagocytic activity of macrophages, activation of NK cells, stimulation of cytotoxic T-lymphocytes, and the upregulation of the Th1 T-helper cell subset. Also increases concentrations of effector proteins such as serum neopterin and 2'5' oligoadenylate synthetase, raises body temperature, and causes reversible decreases in leukocyte and platelet counts. Dacarbazine pharmacodynamics: Dacarbazine is a synthetic analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC). After intravenous administration of dacarbazine, the volume of distribution exceeds total body water content suggesting localization in some body tissue, probably the liver. Its disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours. 1 In a patient with renal and hepatic dysfunctions, the half-lives were lengthened to 55 minutes and 7. 2 hours. 1 The average cumulative excretion of unchanged DTIC in the urine is 40% of the injected dose in 6 hours. 1 DTIC is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations dacarbazine is not appreciably bound to human plasma protein. The mechanism of action of Peginterferon alfa-2b is that it Peginterferon alfa-2b is derived from recombinant human interferon's alfa-2b moeity. It binds to and activates human type 1 interferon receptors causing them to dimerize. This activates the JAK/STAT pathway. Activation of the JAK/STAT pathway increases expression of multiple genes in multiple tissues involved in the innate antiviral response. Peginterferon alfa-2b may also acitvate the nuclear factor κB pathway. The mechanism of action of Dacarbazine is that it The mechanism of action is not known, but appears to exert cytotoxic effects via its action as an alkylating agent. Other theories include DNA synthesis inhibition by its action as a purine analog, and interaction with SH groups. Dacarbazine is not cell cycle-phase specific. Peginterferon alfa-2b absorption: Peginterferon alfa-2b reaches peak plasma concentration 15-44 hours after subcutaneous administration. The mean absorption half-life is 4. 6 hours. After multiple doses the bioavailability of Peginterferon alfa-2b increases with trough concentrations at week 48 3-fold higher than those at week 4. Dacarbazine absorption: Erratic, slow and incomplete. No volume of distribution information is available for Peginterferon alfa-2b. No volume of distribution information is available for Dacarbazine. No protein binding information is available for Peginterferon alfa-2b. Dacarbazine is Less than 5% bound to plasma proteins. No metabolism information is available for Peginterferon alfa-2b. Dacarbazine metabolism: Hepatic. Peginterferon alfa-2b is eliminated via Renal elimination accounts for 30% of Peginterferon alfa-2b elimination. Dacarbazine is eliminated via Dacarbazine is subject to renal tubular secretion rather than glomerular filtration. In man, dacarbazine is extensively degraded. Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine. The half-life of Peginterferon alfa-2b is The mean half-life of elimination of Peginterferon alfa-2b is 40 hours in a range of 22-60 hours. The half-life of Dacarbazine is 5 hours. The clearance of Peginterferon alfa-2b is The estimated apparent clearance of Peginterferon alfa-2b is 22 milliters per hour per kilogram. No clearance information is available for Dacarbazine. Peginterferon alfa-2b toxicity includes Peginterferon alfa-2b may manifest neuropsychiatric complications include suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose. Hypertension, supraventricular arrhythmias, chest pain, and myocardial infarction have been observed in patients using Peginterferon alfa-2b. Peginterferon alfa-2b may produce myelosuppression as well as the development or aggravation of autoimmune disorders including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus. Peginterferon alfa-2b causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with Peginterferon alfa-2b. Peginterferon alfa-2b may decrease or produce loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema and serous retinal detachment. Peginterferon mayy be related to increased ischemic and hemorrhagic cerebrovascular events. Patients with cirrhosis on Peginterferon alfa-2b are at risk of hepatic decompensation. Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis may be induced or aggravated by Peginterferon alfa-2b. Serious and severe infections (bacterial, viral, or fungal) have been reported during treatment with Peginterferon alfa-2b. Ulcerative and hemorrhagic/ischemic colitis have been observed within 12 weeks of starting Peginterferon alfa-2b treatment. Pancreatitis and peripheral nephropathy have also been reported. Peginterferon alfa-2b is associated with growth inhibition in pediatric patients. Use of Peginterferon alfa-2b while pregant may result in delopmental abnormalities or death of the fetus. Dacarbazine toxicity includes LD 50 =350mg/kg (orally in mice). Brand names of Peginterferon alfa-2b include Pegintron, Sylatron. Brand names of Dacarbazine include No brand names available. No synonyms are available for Peginterferon alfa-2b. No synonyms are available for Dacarbazine. Dacarbazin Dacarbazina Dacarbazine Dacarbazinum DTIC ICDMT Peginterferon alfa-2b summary: It is Peginterferon alfa-2b is a purified form of human interferon used to stimulate the innate antiviral response in the treatment of hepatitis B and C, genital warts, and some cancers. Dacarbazine summary: It is Dacarbazine is an antineoplastic agent used to treat malignant melanoma and Hodgkin's disease. Answer: Peginterferon alfa 2b is a limited inhibitor of CYP1A2.

Peginterferon alfa-2b

Drug A is Bromperidol. Drug B is Oxazepam. The severity of the interaction is moderate. The risk or severity of CNS depression can be increased when Oxazepam is combined with Bromperidol. Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. Bromperidol is indicated for No indication available. Oxazepam is indicated for Oxazepam is indicated for the management of anxiety disorders and for the short-term relief of symptoms of anxiety. It may also be used in the management of alcohol withdrawal symptoms. Bromperidol pharmacodynamics: No pharmacodynamics available. Oxazepam pharmacodynamics: Benzodiazepines, including oxazepam, exert their sedative and anxiolytic effects by potentiating the effects of endogenous GABA, the primary inhibitory neurotransmitter in the CNS. Compared to other benzodiazepines, it has relatively low potency and a moderate duration of action. Oxazepam should be administered with caution to patients for whom a drop in blood pressure may lead to cardiac complications as, in rare cases, it may cause hypotension. The mechanism of action of Bromperidol is that it No mechanism of action available. The mechanism of action of Oxazepam is that it Like other benzodiazepines, oxazepam exerts its anxiolytic effects by potentiating the effect of gamma-aminobutyric acid (GABA) on GABA(A) receptors, the main inhibitory neurotransmitter receptors in the mammalian brain. GABA(A) receptors are a component of GABA-gated ionotropic chloride channels that produce inhibitory postsynaptic potentials - following activation by GABA, the channel undergoes a conformational change that allows the passage of chloride ions through the channel. The inhibitory potentials produced by GABA neurotransmission play an integral role in the suppression and control of epileptiform nerve firing such as that seen in epilepsy, which makes the GABA system a desirable target in the treatment of epilepsy. Benzodiazepines are positive allosteric modulators of GABA(A) function. They bind to the interface between alpha (α) and gamma (γ) subunits on the receptor, commonly referred to as the benzodiazepine binding site, and modulate the receptor such that its inhibitory response to GABA binding is dramatically increased. No absorption information is available for Bromperidol. Oxazepam absorption: Following oral administration, peak plasma levels (Cmax ) averaged 450 mg/mL and occurred approximately 3 hours (Tmax ) after dosing. No volume of distribution information is available for Bromperidol. No volume of distribution information is available for Oxazepam. No protein binding information is available for Bromperidol. Oxazepam is Plasma protein binding is approximately 89%, likely to albumin. bound to plasma proteins. No metabolism information is available for Bromperidol. Oxazepam metabolism: Oxazepam has a single major inactive metabolite, a glucuronide conjugate. The glucuronidation of the S-isomer is catalyzed by UGT2B15. The glucuronidation of the R-isomer is catalyzed by UGT2B7 and UGT1A9. Bromperidol is eliminated via No route of elimination available. Oxazepam is eliminated via Oxazepam is primarily eliminated in the urine as its glucuronide metabolite, with the feces containing approximately 21% of the unchanged drug. The majority of an orally ingested dose of oxazepam is excreted within 48 hours. The half-life of Bromperidol is No half-life available. The half-life of Oxazepam is The mean elimination half-life of oxazepam is 8. 2 hours. No clearance information is available for Bromperidol. No clearance information is available for Oxazepam. No toxicity information is available for Bromperidol. Oxazepam toxicity includes The oral LD 50 in rats and mice is >8000 mg/kg and 1540 mg/kg, respectively. Symptoms of oxazepam overdose are likely to be consistent with its adverse effect profile and range from mild to severe, sometimes fatal, CNS depression. Treatment should include gastric decontamination, via lavage or induced vomiting, followed by symptomatic and supportive measures. The benzodiazepine antagonist flumazenil may be used in hospitalized patients as an adjunct to non-pharmacological management, but may increase the risk of seizure in long-term benzodiazepine users and in cyclic antidepressant overdose. Brand names of Bromperidol include No brand names available. Brand names of Oxazepam include Oxpam. No synonyms are available for Bromperidol. No synonyms are available for Oxazepam. Oxazepam Bromperidol summary: It is Bromperidol is a first-generation butyrophenone antipsychotic used in the treatment of schizophrenia and other psychotic manifestations. Oxazepam summary: It is Oxazepam is an intermediate-acting benzodiazepine with slow onset commonly used to treat panic disorders, severe anxiety, alcohol withdrawals, and insomnia. Answer: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

Bromperidol

Drug A is Bumetanide. Drug B is Doxazosin. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Doxazosin is combined with Bumetanide. Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. Bumetanide is indicated for the treatment of edema associated with congestive heart failure, hepatic and renal disease including the nephrotic syndrome. Doxazosin is indicated for Doxazosin is indicated to treat the symptoms of benign prostatic hypertrophy, which may include urinary frequency, urgency, and nocturia, among other symptoms. In addition, doxazosin is indicated alone or in combination with various antihypertensive agents for the management of hypertension. Off-label uses of doxazosin include the treatment of pediatric hypertension and the treatment of ureteric calculi. Bumetanide pharmacodynamics: Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in patients in whom high doses of furosemide are ineffective. There is however no reason not to use bumetanide as a first choice drug. The main difference between the two substances is in bioavailability. Bumetanide has more predictable pharmacokinetic properties as well as clinical effect. In patients with normal renal function, bumetanide is 40 times more effective than furosemide. Doxazosin pharmacodynamics: Doxazosin decreases standing and supine blood pressure and relieves the symptoms of benign prostatic hypertrophy through the inhibition of alpha-1 receptors. Doxazosin may cause hypotension due to its pharmacological actions. This frequently occurs in the upright position, leading to a feeling of dizziness or lightheadedness. The first dose of doxazosin may lead to such effects, however, subsequent doses may also cause them. The risk of these effects is particularly high when dose adjustments occur or there are long intervals between doxazosin doses. Treatment should be started with the 1 mg dose of doxazosin, followed by slow titration to the appropriate dose. Patients must be advised of this risk and to avoid situations in which syncope and dizziness could be hazardous following the ingestion of doxazosin. Interestingly doxazosin exerts beneficial effects on plasma lipids. It reduces LDL (low-density lipoprotein) cholesterol and triglyceride levels and increases HDL (high-density lipoprotein) cholesterol levels. A note on priapism risk In rare cases, doxazosin and other alpha-1 blockers may cause priapism, a painful occurrence of persistent and unrelievable penile erection that can lead to impotence if medical attention is not sought as soon as possible. Patients must be advised of the priapism risk associated with doxazosin and to seek medical attention immediately if it is suspected. The mechanism of action of Bumetanide is that it Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. The mechanism of action of Doxazosin is that it Doxazosin selectively inhibits the postsynaptic alpha-1 receptors on vascular smooth muscle by nonselectively blocking the alpha-1a, alpha-1b, and alpha-1d subtypes. This action on blood vessels decreases systemic peripheral vascular resistance, reducing blood pressure, exerting minimal effects on the heart rate due to its receptor selectivity. Norepinephrine-activated alpha-1 receptors located on the prostate gland and bladder neck normally cause contraction of regional muscular tissue, obstructing urinary flow and contributing to the symptoms of benign prostatic hypertrophy. Alpha-1 antagonism causes smooth muscle relaxation in the prostate and bladder, effectively relieving urinary frequency, urgency, weak urinary stream, and other unpleasant effects of BPH. Recently, doxazosin was found to cause apoptosis of hERG potassium channels in an in vitro setting, possibly contributing to a risk of heart failure with doxazosin use. Bumetanide absorption: Bumetanide is completely absorbed (80%), and the absorption is not altered when taken with food. Bioavailability is almost complete. Doxazosin absorption: Doxazosin is rapidly absorbed in the gastrointestinal tract and peak concentrations are achieved within 2-3 hours after administration. The bioavailability is about 60%-70%. The intake of food with doxazosin is not expected to cause clinically significant effects. No volume of distribution information is available for Bumetanide. The volume of distribution of Doxazosin is The volume of distribution of doxazosin is 1. 0-1. 9 L/kg. In a study of radiolabeled doxazosin administered to pregnant rats, doxazosin was found to cross the placenta. Bumetanide is 97% bound to plasma proteins. Doxazosin is The plasma protein binding of doxazosin is estimated at 98%. It has also been shown to be bound to the alpha-1 acid glycoprotein. bound to plasma proteins. Bumetanide metabolism: 45% is secreted unchanged. Urinary and biliary metabolites are formed by oxidation of the N-butyl side chain. Doxazosin metabolism: Hepatic metabolism of doxazosin produces inactive O-demethylated and C-hydroxylated metabolites. Metabolism occurs via O-demethylation of the quinazoline nucleus of doxazosin or via hydroxylation of its benzodioxan portion. The enzymes involved in the metabolism of doxazosin include CYP2C19, CYP2D6, CYP2C19, and CYP3A4, which is the primary metabolizing enzyme. Doxazosin itself is considered to be mainly responsible for its pharmacological action, however, some active metabolites have been identified whose pharmacokinetics have not been adequately characterized. Bumetanide is eliminated via Oral administration of carbon-14 labeled Bumex to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Biliary excretion of Bumex amounted to only 2% of the administered dose. Doxazosin is eliminated via In a pharmacokinetic study using a 1 mg IV radiolabeled dose and a 2 mg oral dose, 63% of the ingested doxazosin was found to be excreted in the feces and about 9% of the dose was found to be excreted in the urine. Traces of radiolabeled unchanged drug were found in the urine and about 5% of the administered drug was found as unchanged drug excreted in the feces. The half-life of Bumetanide is 60-90 minutes. The half-life of Doxazosin is The terminal elimination half-life of doxazosin has been estimated at 9-12 hours according to some resources. The FDA label indicates the elimination half-life of doxazosin is 22 hours. The clearance of Bumetanide is 0. 2 - 1. 1 mL/min/kg [preterm and full-term neonates with respiratory disorders]. 2. 17 mL/min/kg [neonates receiving bumetanide for volume overload] 1. 8 +/- 0. 3 mL/min/kg [geriatric subjects] 2. 9 +/- 0. 2 mL/min/kg [younger subjects] The clearance of Doxazosin is The clearance of doxazosin is low and ranges from approximately 1-2 ml/min/kg. Bumetanide toxicity includes Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels. Doxazosin toxicity includes LD50 information The oral LD50 of doxazosin in mice is >1000 mg/kg. Overdose information Symptoms of overdose include hypotension, changes in heart rate, and drowsiness. Administer supportive treatment in case of an overdose with doxazosin. Remove unabsorbed doxazosin from the gastrointestinal tract, correct hypotension, and closely monitor vital signs. Brand names of Bumetanide include Bumex, Burinex. Brand names of Doxazosin include Cardura. No synonyms are available for Bumetanide. Bumetanide Bumetanidum No synonyms are available for Doxazosin. Doxazosina Doxazosine Doxazosinum Bumetanide summary: It is Bumetanide is a sulfamyl diuretic used to treat edema in congestive heart failure, hepatic and renal disease, and nephrotic syndrome. Doxazosin summary: It is Doxazosin is an alpha-1 adrenergic receptor used to treat mild to moderate hypertension and urinary obstruction due to benign prostatic hyperplasia. Answer: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects.

Bumetanide

Drug A is Pembrolizumab. Drug B is Estradiol valerate. The severity of the interaction is minor. Estradiol valerate may increase the thrombogenic activities of Pembrolizumab. Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. Pembrolizumab is indicated for Pembrolizumab is indicated for the following conditions: Melanoma for the treatment of patients with unresectable or metastatic melanoma (adult patients in the US and patients ≥12 years old in the EU) for the adjuvant treatment of adult and pediatric patients 12 years of age and older with Stage IIB, IIC, or III melanoma following complete resection Non-Small Cell Lung Cancer (NSCLC) in combination with pemetrexed and platinum-based chemotherapy as a first-line treatment for patients with metastatic nonsquamous NSCLC with no EGFR or ALK mutations in combination with carboplatin and paclitaxel as a first-line treatment for patients with metastatic squamous NSCLC as a monotherapy for the first-line treatment of NSCLC expressing PD-L1 with no EGFR or ALK mutations in patients with metastatic disease or stage III disease who are not candidates for surgery or chemoradiation as a monotherapy for the treatment of NSCLC expressing PD-L1 with disease progression on or after platinum-based chemotherapy - this includes patients with EGFR or ALK mutations, providing they have experienced disease progression on prior FDA-approved therapy for these aberrations in combination with platinum-based chemotherapy for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery Head and Neck Squamous Cell Cancer (HNSCC) in combination with fluorouracil and platinum-based chemotherapy as a first-line treatment for patients with metastatic or recurrent, unresectable HNSCC as a monotherapy for the first-line treatment of patients with metastatic or recurrent, unresectable HNSCC expressing PD-L1 as a monotherapy for the treatment of patients with metastatic or recurrent HNSCC with disease progression on or after platinum-based chemotherapy Classical Hodgkin Lymphoma (cHL) for the treatment of adult patients with relapsed or refractory cHL for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed following ≥2 lines of therapy Primary Mediastinal Large B-cell Lymphoma (PMBCL) for the treatment of adult and pediatric patients with refractory PMBCL, or PMBCL that has relapsed following ≥2 lines of therapy Urothelial Carcinoma for the treatment of locally advanced or metastatic urothelial carcinoma in patients ineligible for platinum-based chemotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-based chemotherapy or within 12 months of adjuvant/neoadjuvant platinum-based chemotherapy for the treatment of BCG vaccine -unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ, with or without papillary tumors, who are not candidates for cystectomy for the treatment of locally advanced or metastatic urothelial carcinoma in combination with enfortumab vedotin in adult patients ineligible for platinum-based chemotherapy under the accelerated approval from the FDA Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient Cancer (dMMR) as a last-line therapy for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer Gastric Cancer in combination with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy, as a first-line treatment for patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD -L1 (CPS ≥1) as determined by an FDA-approved test in combination with fluoropyrimidine - and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma Esophageal Cancer in combination with fluoropyrimidine- and platinum-based chemotherapy for the treatment of patients with locally advanced or metastatic esophageal or GEJ carcinoma who are not candidates for surgery or definitive chemoradiation as a monotherapy for the treatment of locally advanced or metastatic esophageal or GEJ carcinoma expressing PD-L1 in patients who are not candidates for surgery or definitive chemoradiation Cervical Cancer in combination with other chemotherapies, with or without bevacizumab, for the treatment of persistent, recurrent, or metastatic cervical cancer expressing PD-L1 as a monotherapy for the treatment of recurrent or metastatic cervical cancer expressing PD-L1 in patients who have experienced disease progression on or after previous chemotherapy in combination with chemoradiotherapy for the treatment of patients with FIGO 2014 Stage III -IVA cervical cancer Hepatocellular Carcinoma (HCC) as a monotherapy for the treatment of HCC in patients who have been previously treated with sorafenib Biliary Tract Cancer (BTC) in combination with gemcitabine and cisplatin for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer Merkel Cell Carcinoma (MCC) for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic MCC Renal Cell Carcinoma (RCC) in combination with either axitinib or lenvatinib as a first-line treatment for adult patients with advanced RCC for the adjuvant treatment of patients with RCC who are at an intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions Endometrial Carcinoma in combination with lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR who experience disease progression following prior systemic therapy and who are not candidates for surgery or radiation therapy as a monotherapy for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation Tumor Mutational Burden-High (TMB-H) Cancer as a last-line therapy for the treatment of adult and pediatric patients with unresectable or metastatic TMB-H solid tumors that have progressed following prior treatment Cutaneous Squamous Cell Carcinoma (cSCC) for the treatment of patients with recurrent or metastatic sCC, or locally advanced sCC that is not curable with surgery or radiation therapy Triple-Negative Breast Cancer (TNBC) for the treatment of patients with high-risk early-stage TNBC, in combination with chemotherapy as a neoadjuvant treatment followed by continued use as a single adjuvant agent following surgery in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic TNBC expressing PD-L1 For all approved adult indications, pembrolizumab may be used for an additional 6 weeks at 400mg weekly. Estradiol valerate is indicated for Estradiol valerate is commercially available as an intramuscular injection as the product Delestrogen and is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding. Pembrolizumab pharmacodynamics: Pembrolizumab exerts its pharmacologic effects by releasing PD-1 pathway-mediated inhibition of the immune response, which in turn improves the anti-tumor immune response. Due to its relatively broad mechanism of action, it is useful in the treatment of a wide variety of cancers. Pembrolizumab can cause immune-mediated adverse reactions - including hepatitis, nephritis, and pneumonitis - in any organ system or tissue. Careful monitoring of the patient (including laboratory evaluation of liver, kidney, and thyroid function) should occur at baseline and periodically throughout therapy to monitor for emerging immune-mediated reactions. Estradiol valerate pharmacodynamics: Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects. The mechanism of action of Pembrolizumab is that it Pembrolizumab binds with high affinity to the cell surface receptor programmed cell death protein 1 (PD-1) and antagonizes its interaction with its known ligands PD-L1 and PD-L2. Under normal circumstances, the binding of the ligands of PD-1 to the receptor inhibits the TCR-mediated T-cell proliferation and cytokine production. This inhibitory signal appears to play a role in self-tolerance and collateral damage minimization after immune responses against a pathogen and maternal tolerance to fetal tissue. The binding of pembrolizumab to PD-1 prevents this inhibitory pathway, causing a physiological shift towards immune reactivity and enhancing tumor immunosurveillance and anti-tumor immune response. The mechanism of action of Estradiol valerate is that it Estradiol enters target cells freely (e. g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause, which are primarily caused by a loss of estrogenic activity. Pembrolizumab absorption: Intravenously administered pembrolizumab is completely bioavailable. Steady-state is reached after approximately 16 weeks. Estradiol valerate absorption: IM Injection: When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. Natazia: After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites, estrone and other metabolites. Maximum serum estradiol concentrations of 73. 3 pg/mL are reached at a median of approximately 6 hours (range: 1. 5–12 hours) and the area under the estradiol concentration curve [AUC(0–24h)] was 1301 pg·h/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day 1 of the 28-day sequential regimen. The volume of distribution of Pembrolizumab is The steady-state volume of distribution of pembrolizumab is approximately 6 liters. No volume of distribution information is available for Estradiol valerate. Pembrolizumab is Pembrolizumab is not expected to bind to plasma proteins. bound to plasma proteins. No protein binding information is available for Estradiol valerate. Pembrolizumab metabolism: Pembrolizumab is catalyzed into smaller peptides and amino acids via general protein degradation. Estradiol valerate metabolism: Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450. Pembrolizumab is eliminated via No route of elimination available. Estradiol valerate is eliminated via Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life of Pembrolizumab is The terminal half-life of pembrolizumab is 22 days. The half-life of Estradiol valerate is No half-life available. The clearance of Pembrolizumab is Clearance is moderately lower at steady-state (195 mL/day) than after the first dose (252 mL/day), although this decrease is not clinically significant. No clearance information is available for Estradiol valerate. Pembrolizumab toxicity includes There are no data regarding overdosage with pembrolizumab. No toxicity information is available for Estradiol valerate. Brand names of Pembrolizumab include Keytruda. Brand names of Estradiol valerate include Delestrogen, Natazia. No synonyms are available for Pembrolizumab. No synonyms are available for Estradiol valerate. Pembrolizumab summary: It is Pembrolizumab is a PD-1 blocking antibody used to treat various types of cancer, including metastatic melanoma, non small-cell lung cancer, cervical cancer, head and neck cancer, and Hodgkin's lymphoma. Estradiol valerate summary: It is Estradiol valerate is an estradiol prodrug used to treat some effects of menopause, hypoestrogenism, androgen dependant carcinoma of the prostate, and in combination products for endometriosis and contraception. Answer: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders.

Pembrolizumab

Drug A is Acetylcysteine. Drug B is Levosalbutamol. The severity of the interaction is minor. The excretion of Levosalbutamol can be decreased when combined with Acetylcysteine. Co-administration OATP1B1 substrates with inhibitors of that transporter may lead to increased serum concentrations of the substrates due to attenuated transporter-mediated efflux. Altered pharmacokinetics of the substrates may result in altered clinical efficacy and increased risk for developing drug-related adverse reactions. Acetylcysteine is indicated for Acetylcysteine is indicated for mucolytic therapy and in the management of acetaminophen overdose. Levosalbutamol is indicated for Indicated for the management of COPD (chronic obstructive pulmonary disease, also known as chronic obstructive lung disease) and asthma. Acetylcysteine pharmacodynamics: Acetylcysteine is indicated for mucolytic therapy and in the management of acetaminophen overdose. It has a short duration of action as it is given every 1-8 hours depending on route of administration, and has a wide therapeutic window. Patients should be counselled regarding diluting oral solutions in cola for taste masking, the risk of hypersensitivity, and the risk of upper gastrointestinal hemorrhage. Levosalbutamol pharmacodynamics: It acts by relaxing smooth muscle in the bronchial tubes to increase air flow and relieve acute shortness of breath. The mechanism of action of Acetylcysteine is that it A number of possible mechanisms for the mucolytic activity of acetylcysteine have been proposed. Acetylcysteine's sulfhydryl groups may hydrolize disulfide bonds within mucin, breaking down the oligomers, and making the mucin less viscous. Acetylcysteine has also been shown to reduce mucin secretion in rat models. It is an antioxidant in its own right but is also deacetylated to cysteine, which participates in the synthesis of the antioxidant glutathione. The antioxidant activity may also alter intracellular redox reactions, decreasing phosphorylation of EGFR and MAPK, which decrease transcription of the gene MUC5AC which produces mucin. In the case of acetaminophen overdoses, a portion of the drug is metabolized by CYP2E1 to form the potentially toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). The amount of NAPQI produced in an overdose saturates and depletes glutathione stores. The free NAPQI promiscuously binds to proteins in hepatocytes, leading to cellular necrosis. Acetylcysteine can directly conjugate NAPQI or provide cysteine for glutathione production and NAPQI conjugation. The mechanism of action of Levosalbutamol is that it β2 adrenergic receptors on airway smooth muscle are Gs coupled and their activation by levosalbutamol leads to activation of adenylate cyclase and to an increase in the intracellular concentration of 3',5'-cyclic adenosine monophosphate (cyclic AMP). Increased cyclic AMP activates protein kinase A which itself inhibits the phosphorylation of myosin produces lower intracellular ionic calcium concentrations, inducing muscle relaxation. Increased cyclic AMP concentrations are also associated with the inhibition of the release of mediators from mast cells in the airways, potentially contributing to its benefit in asthma attacks. Acetylcysteine absorption: An 11 g dose in the form of an effervescent tablet for solution reaches a mean Cmax of 26. 5 µg/mL, with a Tmax of 2 hours, and an AUC of 186 µg*h/mL. Levosalbutamol absorption: Inhalation delivers the medication directly into the airways and lungs, thereby minimizing side effects because of reduced systemic absorption of the inhaled medications. The volume of distribution of Acetylcysteine is The volume of distribution of acetylcysteine is 0. 47 L/kg. No volume of distribution information is available for Levosalbutamol. Acetylcysteine is Acetylcysteine is 66-97% protein bound in serum, usually to albumin. bound to plasma proteins. Levosalbutamol is plasma protein binding is relatively low. bound to plasma proteins. Acetylcysteine metabolism: Acetylcysteine can be deacetylated by aminoacylase 1 or other undefined deacetylases before undergoing the normal metabolism of cysteine. Levosalbutamol metabolism: Pure (R)-salbutamol formulation known as levosalbutamol is metabolised up to 12 times faster than (S)-salbutamol by intestine. Acetylcysteine is eliminated via An oral dose of radiolabelled acetylcysteine is 13-38% recovered in the urine in the first 24 hours, while 3% is recovered in the feces. Levosalbutamol is eliminated via excreted into the urine. The half-life of Acetylcysteine is The mean terminal half life of acetylcysteine in adults is 5. 6 hours and in pre-term neonates is 11 hours. The half-life of Levosalbutamol is 3. 3 - 4 hours. The clearance of Acetylcysteine is Acetylcysteine has a mean clearance of 0. 11 L/hr/kg. No clearance information is available for Levosalbutamol. Acetylcysteine toxicity includes Patients experiencing an overdose may present with vomiting, nausea, bronchospasm, periorbital angioedema, and hypotension. Treat patients with symptomatic and supportive measures. Hemodialysis may remove some acetylcysteine from circulation as it is somewhat protein bound. No toxicity information is available for Levosalbutamol. Brand names of Acetylcysteine include Acetadote. Brand names of Levosalbutamol include Xopenex. No synonyms are available for Acetylcysteine. Acetilcisteina Acetylcysteine Acetylcysteinum L-acetylcysteine Mercapturic acid N-acetylcysteine No synonyms are available for Levosalbutamol. Levalbuterol Levosalbutamol R-salbutamol Acetylcysteine summary: It is Acetylcysteine is a medication that can be used as a mucolytic in patients with certain lung conditions and as an antidote for acetaminophen overdose. Levosalbutamol summary: It is Levosalbutamol is a beta-2 adrenergic receptor agonist used to treat COPD and asthma. Answer: Co-administration OATP1B1 substrates with inhibitors of that transporter may lead to increased serum concentrations of the substrates due to attenuated transporter-mediated efflux. Altered pharmacokinetics of the substrates may result in altered clinical efficacy and increased risk for developing drug-related adverse reactions.

Acetylcysteine

Drug A is Acarbose. Drug B is Flunarizine. The severity of the interaction is moderate. The risk or severity of hypoglycemia can be increased when Flunarizine is combined with Acarbose. The results of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study demonstrated that the use of calcium channel blockers, and verapamil in particular, was associated with lower fasting blood glucose levels in patients with diabetes. Moreover, serum glucose was substantially lower in diabetic patients who used a combination of calcium channel blockers (including verapamil) and blood glucose lowering agents like oral agents and/or insulin alone. In particular, it is believed that calcium channel blockers, and in particular verapamil, are capable of decreasing the expression of thioredoxin interacting protien (TXNIP), which results in a variety of activities such as decreased beta-cell apoptosis, increased beta-cell mass, and enhanced endogenous insulin levels. Acarbose is indicated for Acarbose is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Flunarizine is indicated for Used in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy. Acarbose pharmacodynamics: Acarbose is a complex oligosaccharide that competitively inhibits the ability of brush-border alpha-glucosidase enzymes to break down ingested carbohydrates into absorbable monosaccharides, reducing carbohydrate absorption and subsequent postprandial insulin levels. Acarbose requires the co-administration of carbohydrates in order to exert its therapeutic effect, and as such should be taken with the first bite of a meal three times daily. Given its mechanism of action, acarbose in isolation poses little risk of contributing to hypoglycemia - this risk is more pronounced, however, when acarbose is used in conjunction with other antidiabetic therapies (e. g. sulfonylureas, insulin). Patients maintained on acarbose in addition to other antidiabetic agents should be aware of the symptoms and risks of hypoglycemia and how to treat hypoglycemic episodes. There have been rare post-marketing reports of the development of pneumatosis cystoides intestinalis following treatment with alpha-glucosidase inhibitors - patients experiencing significant diarrhea/constipation, mucus discharge, and/or rectal bleeding should be investigated and, if pneumatosis cystoides intestinalis is suspected, should discontinue therapy. Flunarizine pharmacodynamics: Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. The mechanism of action of Acarbose is that it Alpha-glucosidase enzymes are located in the brush-border of the intestinal mucosa and serve to metabolize oligo-, tri-, and disaccharides (e. g. sucrose) into smaller monosaccharides (e. g. glucose, fructose) which are more readily absorbed. These work in conjunction with pancreatic alpha-amylase, an enzyme found in the intestinal lumen that hydrolyzes complex starches to oligosaccharides. Acarbose is a complex oligosaccharide that competitively and reversibly inhibits both pancreatic alpha-amylase and membrane-bound alpha-glucosidases - of the alpha-glucosidases, inhibitory potency appears to follow a rank order of glucoamylase > sucrase > maltase > isomaltase. By preventing the metabolism and subsequent absorption of dietary carbohydrates, acarbose reduces postprandial blood glucose and insulin levels. The mechanism of action of Flunarizine is that it Flunarizine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Acarbose absorption: The oral bioavailability of acarbose is extremely minimal, with less than 1-2% of orally administered parent drug reaching the systemic circulation. Despite this, approximately 35% of the total radioactivity from a radiolabeled and orally administered dose of acarbose reaches the systemic circulation, with peak plasma radioactivity occurring 14-24 hours after dosing - this delay is likely reflective of metabolite absorption rather than absorption of the parent drug. As acarbose is intended to work within the gut, its minimal degree of oral bioavailability is therapeutically desirable. Flunarizine absorption: 85% following oral administration. No volume of distribution information is available for Acarbose. No volume of distribution information is available for Flunarizine. Acarbose is As only 1-2% of an orally administered dose is absorbed into the circulation, acarbose is unlikely to be subject to clinically relevant protein binding. bound to plasma proteins. Flunarizine is 99% bound to plasma proteins bound to plasma proteins. Acarbose metabolism: Acarbose is extensively metabolized within the gastrointestinal tract, primarily by intestinal bacteria and to a lesser extent by digestive enzymes, into at least 13 identified metabolites. Approximately 1/3 of these metabolites are absorbed into the circulation where they are subsequently renally excreted. The major metabolites appear to be methyl, sulfate, and glucuronide conjugates of 4-methylpyrogallol. Only one metabolite - resulting from the cleavage of a glucose molecule from acarbose - has been identified as having alpha-glucosidase inhibitory activity. Flunarizine metabolism: Hepatic, to two metabolites via N-dealylation and hydroxylation. Acarbose is eliminated via Roughly half of an orally administered dose is excreted in the feces within 96 hours of administration. What little drug material is absorbed into the systemic circulation (approximately 34% of an orally administered dose) is excreted primarily by the kidneys, suggesting renal excretion would be a significant route of elimination if the parent drug was more readily absorbed - this is further supported by data in which approximately 89% of an intravenously administered dose of acarbose was excreted in the urine as active drug (in comparison to <2% following oral administration) within 48 hours. Flunarizine is eliminated via No route of elimination available. The half-life of Acarbose is In healthy volunteers, the plasma elimination half-life of acarbose is approximately 2 hours. The half-life of Flunarizine is 18 days. No clearance information is available for Acarbose. No clearance information is available for Flunarizine. Acarbose toxicity includes The symptoms of acarbose overdose are likely to be consistent with its adverse effect profile and may therefore include significant gastrointestinal (GI) symptoms (flatulence, distension, etc), although an overdose on an empty stomach (i. e. when not co-administered with food) is less likely to result in these GI symptoms. In the event of an overdose, patients should be instructed to avoid carbohydrate-containing foods for 4-6 hours following administration as these can precipitate the aforementioned GI symptoms. Flunarizine toxicity includes -Flunarizine should be used with care in patients with depression or those being prescribed other agents, such as phenothiazines, concurrently, which may cause extrapyramidal side-effects. -Acute overdosage has been reported and the observed symptoms were sedation, agitation and tachycardia. -Treatment of acute overdosage consists of charcoal administration, induction of emesis or gastric lavage, and supportive measures. No specific antidote is known. Brand names of Acarbose include Precose. Brand names of Flunarizine include No brand names available. No synonyms are available for Acarbose. No synonyms are available for Flunarizine. Flunarizine Flunarizinum Acarbose summary: It is Acarbose is an alpha-glucosidase inhibitor used in adjunctly with diet and exercise for the management of glycemic control in patients with type 2 diabetes mellitus. Flunarizine summary: It is Flunarizine is a selective calcium-entry blocker used as migraine prophylaxis in patients with severe and frequent episodes who have not responded adequately to more common treatments. Answer: The results of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study demonstrated that the use of calcium channel blockers, and verapamil in particular, was associated with lower fasting blood glucose levels in patients with diabetes. Moreover, serum glucose was substantially lower in diabetic patients who used a combination of calcium channel blockers (including verapamil) and blood glucose lowering agents like oral agents and/or insulin alone. In particular, it is believed that calcium channel blockers, and in particular verapamil, are capable of decreasing the expression of thioredoxin interacting protien (TXNIP), which results in a variety of activities such as decreased beta-cell apoptosis, increased beta-cell mass, and enhanced endogenous insulin levels.

Acarbose

Drug A is Acetylcysteine. Drug B is Caspofungin. The severity of the interaction is minor. The excretion of Caspofungin can be decreased when combined with Acetylcysteine. Co-administration OATP1B1 substrates with inhibitors of that transporter may lead to increased serum concentrations of the substrates due to attenuated transporter-mediated efflux. Altered pharmacokinetics of the substrates may result in altered clinical efficacy and increased risk for developing drug-related adverse reactions. Acetylcysteine is indicated for Acetylcysteine is indicated for mucolytic therapy and in the management of acetaminophen overdose. Caspofungin is indicated for the treatment of esophageal candidiasis and invasive aspergillosis in patients who are refractory to or intolerant of other therapies. Acetylcysteine pharmacodynamics: Acetylcysteine is indicated for mucolytic therapy and in the management of acetaminophen overdose. It has a short duration of action as it is given every 1-8 hours depending on route of administration, and has a wide therapeutic window. Patients should be counselled regarding diluting oral solutions in cola for taste masking, the risk of hypersensitivity, and the risk of upper gastrointestinal hemorrhage. Caspofungin pharmacodynamics: Caspofungin is an antifungal drug, and belongs to a new class termed the echinocandins. It is used to treat Aspergillus and Candida infection, and works by inhibiting cell wall synthesis. Antifungals in the echinocandin class inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-beta glucan synthase. There is a potential for resistance development to occur, however in vitro resistance development to Caspofungin by Aspergillus species has not been studied. The mechanism of action of Acetylcysteine is that it A number of possible mechanisms for the mucolytic activity of acetylcysteine have been proposed. Acetylcysteine's sulfhydryl groups may hydrolize disulfide bonds within mucin, breaking down the oligomers, and making the mucin less viscous. Acetylcysteine has also been shown to reduce mucin secretion in rat models. It is an antioxidant in its own right but is also deacetylated to cysteine, which participates in the synthesis of the antioxidant glutathione. The antioxidant activity may also alter intracellular redox reactions, decreasing phosphorylation of EGFR and MAPK, which decrease transcription of the gene MUC5AC which produces mucin. In the case of acetaminophen overdoses, a portion of the drug is metabolized by CYP2E1 to form the potentially toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). The amount of NAPQI produced in an overdose saturates and depletes glutathione stores. The free NAPQI promiscuously binds to proteins in hepatocytes, leading to cellular necrosis. Acetylcysteine can directly conjugate NAPQI or provide cysteine for glutathione production and NAPQI conjugation. The mechanism of action of Caspofungin is that it Caspofungin inhibits the synthesis of beta-(1,3)-D-glucan, an essential component of the cell wall of Aspergillus species and Candida species. beta-(1,3)-D-glucan is not present in mammalian cells. The primary target is beta-(1,3)-glucan synthase. Acetylcysteine absorption: An 11 g dose in the form of an effervescent tablet for solution reaches a mean Cmax of 26. 5 µg/mL, with a Tmax of 2 hours, and an AUC of 186 µg*h/mL. Caspofungin absorption: 92% tissue distribution within 36-48 hours after intravenous infusion. The volume of distribution of Acetylcysteine is The volume of distribution of acetylcysteine is 0. 47 L/kg. No volume of distribution information is available for Caspofungin. Acetylcysteine is Acetylcysteine is 66-97% protein bound in serum, usually to albumin. bound to plasma proteins. Caspofungin is 97% bound to plasma proteins. Acetylcysteine metabolism: Acetylcysteine can be deacetylated by aminoacylase 1 or other undefined deacetylases before undergoing the normal metabolism of cysteine. Caspofungin metabolism: Metabolized slowly by hydrolysis and N-acetylation. Acetylcysteine is eliminated via An oral dose of radiolabelled acetylcysteine is 13-38% recovered in the urine in the first 24 hours, while 3% is recovered in the feces. Caspofungin is eliminated via After single intravenous administration of [3H] caspofungin acetate, excretion of caspofungin and its metabolites in humans was 35% of dose in feces and 41% of dose in urine. The half-life of Acetylcysteine is The mean terminal half life of acetylcysteine in adults is 5. 6 hours and in pre-term neonates is 11 hours. The half-life of Caspofungin is 9-11 hours. The clearance of Acetylcysteine is Acetylcysteine has a mean clearance of 0. 11 L/hr/kg. The clearance of Caspofungin is 12 mL/min [After single IV administration]. Acetylcysteine toxicity includes Patients experiencing an overdose may present with vomiting, nausea, bronchospasm, periorbital angioedema, and hypotension. Treat patients with symptomatic and supportive measures. Hemodialysis may remove some acetylcysteine from circulation as it is somewhat protein bound. Caspofungin toxicity includes Side effects include rash, swelling, and nausea (rare). Brand names of Acetylcysteine include Acetadote. Brand names of Caspofungin include Cancidas. No synonyms are available for Acetylcysteine. Acetilcisteina Acetylcysteine Acetylcysteinum L-acetylcysteine Mercapturic acid N-acetylcysteine No synonyms are available for Caspofungin. Caspofungina Acetylcysteine summary: It is Acetylcysteine is a medication that can be used as a mucolytic in patients with certain lung conditions and as an antidote for acetaminophen overdose. Caspofungin summary: It is Caspofungin is an echinocandin used to treat a variety of fungal infections. Answer: Co-administration OATP1B1 substrates with inhibitors of that transporter may lead to increased serum concentrations of the substrates due to attenuated transporter-mediated efflux. Altered pharmacokinetics of the substrates may result in altered clinical efficacy and increased risk for developing drug-related adverse reactions.

Acetylcysteine

Drug A is Abacavir. Drug B is Etodolac. The severity of the interaction is minor. Etodolac may decrease the excretion rate of Abacavir which could result in a higher serum level. The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. Abacavir is indicated for Abacavir is indicated in combination with other anti-retroviral agents for the treatment of HIV-1 infection. It is available in a combination product alongside dolutegravir and lamivudine for the treatment of adult and pediatric patients with HIV-1 who weigh ≥10 kg. Etodolac is indicated for acute and long-term management of signs and symptoms of osteoarthritis and rheumatoid arthritis, as well as for the management of pain. Abacavir pharmacodynamics: Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Abacavir is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The concentration of drug necessary to effect viral replication by 50 percent (EC50) ranged from 3. 7 to 5. 8 μM (1 μM = 0. 28 mcg/mL) and 0. 07 to 1. 0 μM against HIV-1IIIB and HIV-1BaL, respectively, and was 0. 26 ± 0. 18 μM against 8 clinical isolates. Abacavir had synergistic activity in cell culture in combination with the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, and the protease inhibitor (PI) amprenavir; and additive activity in combination with the NRTIs didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine. Etodolac pharmacodynamics: Etodolac is an anti-inflammatory agent with analgesic and antipyretic properties. It is used to treat osteoarthritis, rheumatoid arthritis and control acute pain. The therapeutic effects of etodolac are achieved via inhibition of the synthesis of prostaglandins involved in fever, pain, swelling and inflammation. Etodolac is administered as a racemate. As with other NSAIDs, the S-form has been shown to be active while the R-form is inactive. Both enantiomers are stable and there is no evidence of R- to S- conversion in vivo. The mechanism of action of Abacavir is that it Abacavir is a carbocyclic synthetic nucleoside analogue and an antiviral agent. Intracellularly, abacavir is converted by cellular enzymes to the active metabolite carbovir triphosphate, an analogue of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Viral DNA growth is terminated because the incorporated nucleotide lacks a 3'-OH group, which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation. The mechanism of action of Etodolac is that it Similar to other NSAIDs, the anti-inflammatory effects of etodolac result from inhibition of the enzyme cycooxygenase (COX). This decreases the synthesis of peripheral prostaglandins involved in mediating inflammation. Etodolac binds to the upper portion of the COX enzyme active site and prevents its substrate, arachidonic acid, from entering the active site. Etodolac was previously thought to be a non-selective COX inhibitor, but it is now known to be 5 – 50 times more selective for COX-2 than COX-1. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss. Abacavir absorption: Rapid and extensive after oral administration (83% bioavailability, tablet). When a 300 mg tablet is given twice daily to subjects, the peak plasma concentration (Cmax) was 3. 0 ± 0. 89 mcg/mL and the area under the curve (AUC 0-12 hours) was 6. 02 ± 1. 73 mcg•hr/mL. Etodolac absorption: Based on mass balance studies, the systemic bioavailability of etodolac from either the tablet or capsule formulation is at least 80%. The volume of distribution of Abacavir is 0. 86 ± 0. 15 L/kg [IV administration]. The volume of distribution of Etodolac is 390 mL/kg. Abacavir is Moderate (approximately 50%). Binding of abacavir to plasma protein was independent of concentration. bound to plasma proteins. Etodolac is > 99% bound, primarily to albumin bound to plasma proteins. Abacavir metabolism: Hepatic, by alcohol dehydrogenase and glucuronosyltransferase to a 5′-carboxylic acid metabolite and 5′-glucuronide metabolite, respectively. These metabolites have no antiviral activity. Abacavir is not significantly metabolized by cytochrome P450 enzymes. Etodolac metabolism: Etodolac is extensively metabolized in the liver. Renal elimination of etodolac and its metabolites is the primary route of excretion (72%). Metabolites found in urine (with percents of the administered dose) are: unchanged etodolac (1%), etodolac glucuronide (13%), hydroxylated metabolites (6-, 7-, and 8-OH; 5%), hydroxylated metabolite glucuronides (20%), and unidentified metabolites (33%). Fecal excretion accounts for 16% of its elimination. Abacavir is eliminated via Elimination of abacavir was quantified in a mass balance study following administration of a 600-mg dose of 14C-abacavir: 99% of the radioactivity was recovered, 1. 2% was excreted in the urine as abacavir, 30% as the 5′-carboxylic acid metabolite, 36% as the 5′-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose. Renal excretion of unchanged abacavir is a minor route of elimination in humans. Etodolac is eliminated via It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Etodolac is extensively metabolized in the liver. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces (16% of dose). Approximately 1% of a etodolac dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite. The half-life of Abacavir is 1. 54 ± 0. 63 hours. The half-life of Etodolac is Terminal t 1/2, 7. 3 ± 4. 0 hours. Distribution t 1/2, 0. 71 ± 0. 50 hours. The clearance of Abacavir is 0. 80 ± 0. 24 L/hr/kg [asymptomatic, HIV-1-infected adult patients receiving single (IV dose of 150 mg]. The clearance of Etodolac is Oral cl=49. 1 mL/h/kg [Normal healthy adults]. Oral cl=49. 4 mL/h/kg [Healthy males (18-65 years)] Oral cl=35. 7 mL/h/kg [Healthy females (27-65 years)] Oral cl=45. 7 mL/h/kg [Eldery (>65 years)] Oral cl=58. 3 mL/h/kg [Renal impairement (46-73 years)] Oral cl=42. 0 mL/h/kg [Hepatic impairement (34-60 years)] Abacavir toxicity includes Some myocardial degeneration has been noticed in rats and mice. The most commonly reported adverse reactions of at least moderate intensity (incidence ≥10%) in adult HIV-1 clinical trials were nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders. Serious hypersensitivity reactions have been associated with abacavir which has been strongly linked to the presence of the HLA-B*57:01 allele. This reaction manifests itself in patients within the first 6 weeks of treatment. Patients should be tested for the presence of this allele as recommended by the U. S Food and Drug Administration (FDA). Etodolac toxicity includes Selective COX-2 inhibitors have been associated with increased risk of serious cardiovascular events (e. g. myocardial infarction, stroke) in some patients. Current data is insufficient to assess the cardiovascular risk of etodolac. Etodolac may increase blood pressure and/or cause fluid retention and edema. Risk of GI toxicity including bleeding, ulceration and perforation. Risk of direct renal injury, including renal papillary necrosis. Anaphylactoid and serious skin reactions (e. g. exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Common adverse events include abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI bleeding, GI perforation, nausea, peptic ulcer, vomiting, renal function abnormalities, anemia, dizziness, edema, liver function test abnormalities, headache, prolonged bleeding time, pruritus, rash, tinnitus. Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain. Brand names of Abacavir include Epzicom, Kivexa, Triumeq, Trizivir, Ziagen. Brand names of Etodolac include Lodine. No synonyms are available for Abacavir. ABC No synonyms are available for Etodolac. Étodolac Etodolaco Etodolacum Etodolic acid Etodolsäure Abacavir summary: It is Abacavir is an antiviral nucleoside reverse transcriptase inhibitor used in combination with other antiretrovirals for the treatment of HIV. Etodolac summary: It is Etodolac is an NSAID used to treat osteoarthritis and rheumatoid arthritis, as well as acute pain. Answer: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects.

Abacavir

Drug A is Pembrolizumab. Drug B is Benralizumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Pembrolizumab is combined with Benralizumab. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Pembrolizumab is indicated for Pembrolizumab is indicated for the following conditions: Melanoma for the treatment of patients with unresectable or metastatic melanoma (adult patients in the US and patients ≥12 years old in the EU) for the adjuvant treatment of adult and pediatric patients 12 years of age and older with Stage IIB, IIC, or III melanoma following complete resection Non-Small Cell Lung Cancer (NSCLC) in combination with pemetrexed and platinum-based chemotherapy as a first-line treatment for patients with metastatic nonsquamous NSCLC with no EGFR or ALK mutations in combination with carboplatin and paclitaxel as a first-line treatment for patients with metastatic squamous NSCLC as a monotherapy for the first-line treatment of NSCLC expressing PD-L1 with no EGFR or ALK mutations in patients with metastatic disease or stage III disease who are not candidates for surgery or chemoradiation as a monotherapy for the treatment of NSCLC expressing PD-L1 with disease progression on or after platinum-based chemotherapy - this includes patients with EGFR or ALK mutations, providing they have experienced disease progression on prior FDA-approved therapy for these aberrations in combination with platinum-based chemotherapy for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery Head and Neck Squamous Cell Cancer (HNSCC) in combination with fluorouracil and platinum-based chemotherapy as a first-line treatment for patients with metastatic or recurrent, unresectable HNSCC as a monotherapy for the first-line treatment of patients with metastatic or recurrent, unresectable HNSCC expressing PD-L1 as a monotherapy for the treatment of patients with metastatic or recurrent HNSCC with disease progression on or after platinum-based chemotherapy Classical Hodgkin Lymphoma (cHL) for the treatment of adult patients with relapsed or refractory cHL for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed following ≥2 lines of therapy Primary Mediastinal Large B-cell Lymphoma (PMBCL) for the treatment of adult and pediatric patients with refractory PMBCL, or PMBCL that has relapsed following ≥2 lines of therapy Urothelial Carcinoma for the treatment of locally advanced or metastatic urothelial carcinoma in patients ineligible for platinum-based chemotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-based chemotherapy or within 12 months of adjuvant/neoadjuvant platinum-based chemotherapy for the treatment of BCG vaccine -unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ, with or without papillary tumors, who are not candidates for cystectomy for the treatment of locally advanced or metastatic urothelial carcinoma in combination with enfortumab vedotin in adult patients ineligible for platinum-based chemotherapy under the accelerated approval from the FDA Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient Cancer (dMMR) as a last-line therapy for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer Gastric Cancer in combination with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy, as a first-line treatment for patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD -L1 (CPS ≥1) as determined by an FDA-approved test in combination with fluoropyrimidine - and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma Esophageal Cancer in combination with fluoropyrimidine- and platinum-based chemotherapy for the treatment of patients with locally advanced or metastatic esophageal or GEJ carcinoma who are not candidates for surgery or definitive chemoradiation as a monotherapy for the treatment of locally advanced or metastatic esophageal or GEJ carcinoma expressing PD-L1 in patients who are not candidates for surgery or definitive chemoradiation Cervical Cancer in combination with other chemotherapies, with or without bevacizumab, for the treatment of persistent, recurrent, or metastatic cervical cancer expressing PD-L1 as a monotherapy for the treatment of recurrent or metastatic cervical cancer expressing PD-L1 in patients who have experienced disease progression on or after previous chemotherapy in combination with chemoradiotherapy for the treatment of patients with FIGO 2014 Stage III -IVA cervical cancer Hepatocellular Carcinoma (HCC) as a monotherapy for the treatment of HCC in patients who have been previously treated with sorafenib Biliary Tract Cancer (BTC) in combination with gemcitabine and cisplatin for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer Merkel Cell Carcinoma (MCC) for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic MCC Renal Cell Carcinoma (RCC) in combination with either axitinib or lenvatinib as a first-line treatment for adult patients with advanced RCC for the adjuvant treatment of patients with RCC who are at an intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions Endometrial Carcinoma in combination with lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR who experience disease progression following prior systemic therapy and who are not candidates for surgery or radiation therapy as a monotherapy for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation Tumor Mutational Burden-High (TMB-H) Cancer as a last-line therapy for the treatment of adult and pediatric patients with unresectable or metastatic TMB-H solid tumors that have progressed following prior treatment Cutaneous Squamous Cell Carcinoma (cSCC) for the treatment of patients with recurrent or metastatic sCC, or locally advanced sCC that is not curable with surgery or radiation therapy Triple-Negative Breast Cancer (TNBC) for the treatment of patients with high-risk early-stage TNBC, in combination with chemotherapy as a neoadjuvant treatment followed by continued use as a single adjuvant agent following surgery in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic TNBC expressing PD-L1 For all approved adult indications, pembrolizumab may be used for an additional 6 weeks at 400mg weekly. Benralizumab is indicated for Benralizumab is indicated as a maintenance treatment of patients 12 years or older with severe asthma and an eosinophilic phenotype. The pathology of severe asthma with eosinophilic phenotype is also denotated as TH2-high phenotype. The patients with this phenotype are characterized by the expression of IL-5 and IL-13, airway hyperresponsiveness, responsiveness to inhaled corticosteroids, high serum IgE and eosinophilia in blood and airway. In the TH2-high phenotype, IL-5 presents a central role as it is responsible for eosinophil differentiation, survival, activation and migration to the lungs. Pembrolizumab pharmacodynamics: Pembrolizumab exerts its pharmacologic effects by releasing PD-1 pathway-mediated inhibition of the immune response, which in turn improves the anti-tumor immune response. Due to its relatively broad mechanism of action, it is useful in the treatment of a wide variety of cancers. Pembrolizumab can cause immune-mediated adverse reactions - including hepatitis, nephritis, and pneumonitis - in any organ system or tissue. Careful monitoring of the patient (including laboratory evaluation of liver, kidney, and thyroid function) should occur at baseline and periodically throughout therapy to monitor for emerging immune-mediated reactions. Benralizumab pharmacodynamics: Eosinophils are the key target of inflammatory respiratory diseases and they undergo apoptosis in absence of IL-5. Therefore, benralizumab action on the IL-5 receptor in basophils and eosinophils produces the apoptosis and its significant reduction in the blood. On the other hand, Benralizumab binding to natural killer cells FcγRIIIα receptor produces a direct antibody-dependent cell-mediated cytotoxicity. All these effects produce a reduction in eosinophil count in airway mucosa, submucosa, sputum, blood and bone marrow. The mechanism of action of Pembrolizumab is that it Pembrolizumab binds with high affinity to the cell surface receptor programmed cell death protein 1 (PD-1) and antagonizes its interaction with its known ligands PD-L1 and PD-L2. Under normal circumstances, the binding of the ligands of PD-1 to the receptor inhibits the TCR-mediated T-cell proliferation and cytokine production. This inhibitory signal appears to play a role in self-tolerance and collateral damage minimization after immune responses against a pathogen and maternal tolerance to fetal tissue. The binding of pembrolizumab to PD-1 prevents this inhibitory pathway, causing a physiological shift towards immune reactivity and enhancing tumor immunosurveillance and anti-tumor immune response. The mechanism of action of Benralizumab is that it Interleukin-5 (IL-5) induces an eosinophil-mediated inflammatory response by binding to the IL-5 receptor (IL-5R) expressed in eosinophils, basophils and some mast cells. Benralizumab, unlike IL-5 low-affinity binding, binds with high affinity to the domain I of the α-chain of IL-5R and blocks its signaling and the proliferation of IL-5-dependent cell lines. On the other hand, Benralizumab is an afucosylated antibody in the CH2 region which gives it a high affinity for the FcγRIIIa on natural killer cells, macrophages and neutrophils. This binding triggers a magnified apoptosis response in eosinophils via antibody-dependent cell-mediated cytotoxicity. Pembrolizumab absorption: Intravenously administered pembrolizumab is completely bioavailable. Steady-state is reached after approximately 16 weeks. Benralizumab absorption: Subcutaneous administration of Benralizumab presented a dose-proportional pharmacokinetic profile. The administration of 20-200 mg presented an absorption half-life of 3. 6 days with a bioavailability of 58%. It is also reported for Benralizumab a Cmax of 82 mcg/ml and AUC of 775 mcg day/ml. The volume of distribution of Pembrolizumab is The steady-state volume of distribution of pembrolizumab is approximately 6 liters. The volume of distribution of Benralizumab is Pharmacokinetic reports of Benralizumab showed a volume of distribution in a range of 52-93ml/kg. For a 70kg individual, the central volume of distribution of Benralizumab is 3. 2 L while the peripheral volume of distribution is reported to be 2. 5 L. Pembrolizumab is Pembrolizumab is not expected to bind to plasma proteins. bound to plasma proteins. Benralizumab is There is no reports indicating that Benralizumab binds to plasma proteins. bound to plasma proteins. Pembrolizumab metabolism: Pembrolizumab is catalyzed into smaller peptides and amino acids via general protein degradation. Benralizumab metabolism: As any monoclonal IgG antibody, Beralizumab is degraded by proteases widely spread in the body. Pembrolizumab is eliminated via No route of elimination available. Benralizumab is eliminated via Benraluzimab presents a linear pharmacokinetic without target-receptor mediated clearance. The presence of a dose-proportional pharmacokinetics suggests a rapid depletion of the target and an elimination mainly mediated through the reticuloendothelial system. The half-life of Pembrolizumab is The terminal half-life of pembrolizumab is 22 days. The half-life of Benralizumab is The half-life of Benralizumab is estimated to be 15-18 days. The clearance of Pembrolizumab is Clearance is moderately lower at steady-state (195 mL/day) than after the first dose (252 mL/day), although this decrease is not clinically significant. The clearance of Benralizumab is a subject weighting 70kg, the typical systemic clearance is 0. 29L/day. Pembrolizumab toxicity includes There are no data regarding overdosage with pembrolizumab. Benralizumab toxicity includes There are not reports of long-term studies regarding tumorgenesis or carcinogenesis. Fertility studies performed in aminal trials showed no adverse histopathological findings. Brand names of Pembrolizumab include Keytruda. Brand names of Benralizumab include Fasenra. No synonyms are available for Pembrolizumab. No synonyms are available for Benralizumab. Pembrolizumab summary: It is Pembrolizumab is a PD-1 blocking antibody used to treat various types of cancer, including metastatic melanoma, non small-cell lung cancer, cervical cancer, head and neck cancer, and Hodgkin's lymphoma. Benralizumab summary: It is Benralizumab is a monoclonal antibody used to treat eosinophilic asthma. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Pembrolizumab

Drug A is Abatacept. Drug B is Progesterone. The severity of the interaction is moderate. The metabolism of Progesterone can be increased when combined with Abatacept. The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. Abatacept is indicated for Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. Progesterone is indicated for Gelatinized capsules The gelatinized capsules are indicated for use in the prevention of endometrial hyperplasia in non-hysterectomized postmenopausal women who are receiving conjugated estrogens tablets. They are also indicated for use in secondary amenorrhea. Vaginal gel Progesterone gel (8%) is indicated as progesterone supplementation or replacement as part of an Assisted Reproductive Technology (“ART”) treatment for infertile women with progesterone deficiency. The lower concentration progesterone gel (4%) is used in the treatment of secondary amenorrhea, with the use of the 8% concentration if there is no therapeutic response to the 4% gel. Vaginal insert This form is indicated to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women. Injection (intramuscular) This drug is indicated in amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. Tablets, contraceptive The tablet form of progesterone in contraceptive formulations is indicated for the prevention of pregnancy. Abatacept pharmacodynamics: Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. Progesterone pharmacodynamics: Progesterone, depending on concentration and dosage form, and timing of exposure may have several pharmacodynamic effects. These actions, according, to various preparations, are listed below: General effects Progesterone is the main hormone of the corpus luteum and the placenta. It acts on the uterus by changing the proliferative phase to the secretory phase of the endometrium (inner mucous lining of the uterus). This hormone, stimulated by a hormone called luteinizing hormone (LH) is the main hormone during the secretory phase to prepare the corpus luteum and the endometrium for implantation of a fertilized ovum. As the luteal phase concludes, the progesterone hormone sends negative feedback to the anterior pituitary gland in the brain to decrease FSH (follicle stimulating hormone) and LH (luteinizing hormone) levels. This prevents ovulation and maturation of oocytes (immature egg cells). The endometrium then prepares for pregnancy by increasing its vascularity (blood vessels) and stimulating mucous secretion. This process occurs by progesterone stimulating the endometrium to decrease endometrial proliferation, leading to a decreased uterine lining thickness, developing more complex uterine glands, collecting energy in the form of glycogen, and providing more uterine blood vessel surface area suitable for supporting a growing embryo. As opposed to cervical mucous changes observed during the proliferative phase and ovulation, progesterone decreases and thickens the cervical mucus, rendering it less elastic. This change occurs because the fertilization time period has passed, and a specific consistency of mucous amenable to sperm entry is no longer required. Gelatinized capsules Progesterone capsules are an oral dosage form of micronized progesterone which, chemically identical to progesterone of ovarian origin. Progesterone capsules have all the properties of endogenous progesterone with induction of a secretory phase endometrium with gestagenic, antiestrogenic, slightly antiandrogenic and anti-aldosterone effects. Progesterone opposes the effects of estrogen on the uterus, and is beneficial in women with unopposed estrogen exposure, which carries an increased risk of malignancy. Vaginal gel and vaginal insert The gel preparation mimics the effects of naturally occurring progesterone. In the presence of adequate levels of estrogen, progesterone converts a proliferative endometrium into secretory endometrium. This means that the endometrium changes from a growing and thickening stage into a subsequent preparation stage for pregnancy, which involves further preparatory changes. Progesterone is necessary for the development of decidual tissue (specialized tissue amenable to supporting a possible pregnancy). Progesterone is required to increase endometrial receptivity for the implantation of a fertilized embryo. Once an embryo is implanted, progesterone helps to maintain the pregnancy. Injection (intramuscular) Intramuscularly injected progesterone increases serum progesterone and aids in the prevention of endometrial tissue overgrowth due to unopposed estrogen (which leads to abnormal uterine bleeding and sometimes uterine cancer),. In the absence or deficiency of progesterone, the endometrium continually proliferates, eventually outgrowing its limited blood supply, shedding incompletely, and leading to abnormal and/or profuse bleeding as well as malignancy. Tablets, contraceptive Progesterone-only contraceptive tablets prevent conception by suppressing ovulation in about half of users, causing a thickening of cervical mucus to inhibit sperm movement, lowering the midcycle LH and FSH hormone peaks, slowing the movement of the ovum through the fallopian tubes, and causing secretory changes in the endometrium as described above. The mechanism of action of Abatacept is that it Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. The mechanism of action of Progesterone is that it Progesterone binds and activates its nuclear receptor, PR, which plays an important part in the signaling of stimuli that maintain the endometrium during its preparation for pregnancy. Progesterone receptor (PR) is a member of the nuclear/steroid hormone receptor (SHR) family of ligand-dependent transcription factors that is expressed primarily in female reproductive tissue as well as the central nervous system. As a result of its binding its associated steroid hormone, progesterone, the progesterone receptor (PR) modulates the expression of genes that regulate the development, differentiation, and proliferation of target tissues. In humans, PR is found to be highly expressed in the stromal (connective tissue) cells during the secretory phase and during pregnancy. Progesterone may prevent pregnancy by changing the consistency of cervical mucus to be unfavorable for sperm penetration, and by inhibiting follicle-stimulating hormone (FSH), which normally causes ovulation. With perfect use, the first-year failure rate for progestin-only oral contraceptives is approximately 0. 5%. The typical failure rate, however, is estimated to be approximately 5%, due to late or missed pills. Abatacept absorption: When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78. 6%. Progesterone absorption: Oral micronized capsules Following oral administration of progesterone in the micronized soft-gelatin capsule formulation, peak serum concentration was achieved in the first 3 hours. The absolute bioavailability of micronized progesterone is unknown at this time. In postmenopausal women, serum progesterone concentration increased in a dose-proportional and linear fashion after multiple doses of progesterone capsules, ranging from 100 mg/day to 300 mg/day. IM administration After intramuscular (IM) administration of 10 mg of progesterone in oil, the maximum plasma concentrations were achieved in about 8 hours post-injection and plasma concentrations stayed above baseline for approximately 24 hours post-injection. Injections of 10, 25, and 50 mg lead to geometric mean values for maximum plasma concentration (CMAX) of 7, 28, and 50 ng/mL, respectively. Progesterone administered by the intramuscular (IM) route avoids significant first-pass hepatic metabolism. As a result, endometrial tissue concentrations of progesterone achieved with IM administration are higher when compared with oral administration. Despite this, the highest concentrations of progesterone in endometrial tissue are reached with vaginal administration. Note on oral contraceptive tablet absorption Serum progestin levels peak about 2 hours after oral administration of progesterone-only contraceptive tablets, followed by rapid distribution and elimination. By 24 hours after drug administration, serum levels remain near the baseline, making efficacy dependent upon strict adherence to the dosing schedule. Large variations in serum progesterone levels occur among individuals. Progestin-only administration leads to lower steady-state serum progestin levels and a shorter elimination half-life than concurrent administration with estrogens. The volume of distribution of Abatacept is 0. 07 L/kg [RA Patients, IV administration]. 0. 09 L/kg [Healthy Subjects, IV administration] 0. 11 L/kg [RA patients, subcutaneous administration] The volume of distribution of Progesterone is When administered vaginally, progesterone is well absorbed by uterine endometrial tissue, and a small percentage is distributed into the systemic circulation. The amount of progesterone in the systemic circulation appears to be of minimal importance, especially when implantation, pregnancy, and live birth outcomes appear similar for intramuscular and vaginal administration of progesterone. No protein binding information is available for Abatacept. Progesterone is 96%-99% bound to serum proteins, primarily to serum albumin (50%-54%) and transcortin (43%-48%). bound to plasma proteins. No metabolism information is available for Abatacept. Progesterone metabolism: Progesterone is mainly metabolized by the liver. After oral administration, the major plasma metabolites found are 20 a hydroxy-Δ4 a-prenolone and 5 a-dihydroprogesterone. Some progesterone metabolites are found excreted in the bile and these metabolites may be deconjugated and subsequently metabolized in the gut by reduction, dehydroxylation, and epimerization. The major plasma and urinary metabolites are comparable to those found during the physiological progesterone secretion of the corpus luteum. Abatacept is eliminated via Kidney and liver. Progesterone is eliminated via Progesterone metabolites are excreted mainly by the kidneys. Urinary elimination is observed for 95% of patients in the form of glycuroconjugated metabolites, primarily 3 a, 5 ß–pregnanediol ( pregnandiol ). The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the urine and bile. Progesterone metabolites, excreted in the bile, may undergo enterohepatic recycling or may be found excreted in the feces. The half-life of Abatacept is 16. 7 (12-23) days in healthy subjects;. 13. 1 (8-25) days in RA subjects; 14. 3 days when subcutaneously administered to adult RA patients. The half-life of Progesterone is Absorption half-life is approximately 25-50 hours and an elimination half-life of 5-20 minutes (progesterone gel). Progesterone, administered orally, has a short serum half-life (approximately 5 minutes). It is rapidly metabolized to 17-hydroxyprogesterone during its first pass through the liver. The clearance of Abatacept is 0. 23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion]. 0. 22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0. 4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0. 28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. The clearance of Progesterone is Apparent clearance 1367 ± 348 (50mg of progesterone administered by vaginal insert once daily). 106 ± 15 L/h (50mg/mL IM injection once daily). Abatacept toxicity includes Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. Progesterone toxicity includes Intraperitoneal LD50 (rat): 327 mg/kg. Use in pregnancy Only forms of progesterone that are indicated on product labeling for pregnancy should be used. Some forms of progesterone should not be used in pregnancy,. Refer to individual product monographs for information regarding use in pregnancy. Many studies have found no effects on fetal development associated with long-term use of contraceptive doses of oral progestins. Studies of infant growth and development that have been conducted have not demonstrated significant adverse effects, however, these studies are few in number. It is therefore advisable to rule out suspected pregnancy before starting any hormonal contraceptive. Effects on fertility Progesterone at high doses is an antifertility drug and high doses would be expected to impair fertility until cessation. The progesterone contraceptive should not be used during pregnancy. Carcinogenicity Progesterone has been shown to induce or promote the formation of ovarian, uterine, mammary, and genital tract tumors in animals. The clinical relevance of these findings is unknown. Certain epidemiological studies of patients using oral contraceptives have reported an increased relative risk of developing breast cancer, especially at a younger age and associated with a longer duration of use. These studies have mainly involved combined oral contraceptives, and therefore, it is unknown whether this risk is attributable to progestins, estrogens, or a combination of both. At this time, there is insufficient data to determine whether the use of progestin-only contraceptives increases the risk in a similar way to combined contraceptives. A meta-analysis of 54 studies showed a small increase in the frequency of breast cancer diagnosis for women who were currently using combined oral contraceptives, or had used them within the past 10 years. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of hormone use. Women with breast cancer should not use oral contraceptives, as there is no sufficient data to fully establish or negate the risk of cancer with hormonal contraceptive use. Use in breastfeeding Progesterone has been detected in the milk of nursing mothers,. No adverse effects, in general, have been found on breastfeeding ability or on the health, growth, or development of the growing infant. Despite this, isolated post-marketing cases of decreased milk production have been reported. Brand names of Abatacept include Orencia. Brand names of Progesterone include Bijuva, Crinone, Endometrin, Prochieve, Prometrium. No synonyms are available for Abatacept. No synonyms are available for Progesterone. 17alpha-Progesterone Agolutin Akrolutin Corpus Luteum Hormone Gelbkörperhormon Luteohormone Lutogynon Progesteron Progesterona Progestérone Progesterone Progesteronum Abatacept summary: It is Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. Progesterone summary: It is Progesterone is a hormone used for a variety of functions, including contraception, control of abnormal uterine bleeding, maintenance of pregnancy, and prevention of endometrial hyperplasia. Answer: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates.

Abatacept

Drug A is Alteplase. Drug B is Esterified estrogens. The severity of the interaction is moderate. Esterified estrogens may decrease the anticoagulant activities of Alteplase. Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents. Alteplase is indicated for Alteplase is indicated for the treatment of acute ischemic stroke (AIS) and for use in acute myocardial infarction (AMI) for the reduction of mortality and incidence of heart failure. Alteplase is also indicated for the lysis of acute massive pulmonary embolism, defined as acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments, and acute pulmonary emboli accompanied by unstable hemodynamics. Esterified estrogens is indicated for Esterified estrogens are indicated to replace estrogen in women with ovarian failure or other conditions that cause a lack of natural estrogen in the body. It is also indicated for the treatment of symptoms of breast cancer in both men and women. In men it can be used for the treatment of advanced prostate cancer. It is also indicated for the treatment of menopausal symptoms. Alteplase pharmacodynamics: Alteplase binds to fibrin and plasminogen. Alteplase specificity for fibrin is achieved thanks to its high affinity for lysine residues. Also, it can bind plasminogen via loop structures called kringles, stabilized by three disulphide linkages similar to the ones in plasminogen. The specificity of alteplase for plasminogen bound to fibrin allows this drug to act in a clot- or fibrin-specific manner, leading to low concentrations of circulating plasmin and a lower risk of hemorrhagic transformation. In patients with acute myocardial infarction, alteplase reduces fibrinogen levels 3 to 6 hours after treatment. In patients with acute ischemic stroke, patients treated with alteplase have a significantly higher resolution of hyperdense artery sign, a marker of clot formation in the proximal middle cerebral artery, compared to those treated with placebo. The use of alteplase increases the risk of bleeding and thromboembolic events. Rare cases of cholesterol embolism have also been reported. Esterified estrogens pharmacodynamics: Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estradiol is the principle intracellular human estrogen and is more potent than estrone and estriol at the receptor level; it is the primary estrogen secreted prior to menopause. The mechanism of action of Alteplase is that it Alteplase is a recombinant tissue plasminogen activator (rt-PA) that converts plasminogen to plasmin in a fibrin-dependent process. In the absence of fibrin, alteplase converts a limited amount of plasminogen. However, in the presence of fibrin clots, alteplase binds to fibrin and cleaves the arginine-valine bond at positions 560 and 561 of plasminogen, converting it into its active form, plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus and promotes clot dissolution. Alteplase initiates local fibrinolysis with limited systemic proteolysis. The mechanism of action of Esterified estrogens is that it Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system; estrogen replacement reduces elevated levels of these hormones. Alteplase absorption: Healthy volunteers with a baseline endogenous tissue plasminogen activator (t-PA) of 3. 3 ng/ml had a 290-fold increase in baseline concentrations after receiving alteplase at an infusion rate of 0. 25 mg/kg for 30 min; with an infusion rate of 0. 5 mg/kg, a 550-fold increase was observed. Acute myocardial infarction patients (n=12) given 10 mg of alteplase in a 2-minute infusion reached a peak plasma concentration of 3310 ng/ml. This was followed by 50 mg of alteplase in 1 h and 30 mg in 1. 5 h, resulting in steady-state plasma levels of 2210 ng/ml and 930 ng/ml, respectively. Esterified estrogens absorption: Readily absorbed after oral administration. High concentrations of estrone are achieved with oral administration, whereas higher concentrations of estradiol are generally achieved after percutaneous absorption. Although vaginal products (such as gel, rings, etc. ) are administered locally, they achieve high serum concentrations. The volume of distribution of Alteplase is The initial volume of distribution approximates plasma volume. The average volume of distribution of the central compartment goes from 3. 9 to 4. 3 L, and the volume of distribution at steady state goes from 7. 2 to 12 L. The volume of distribution of Esterified estrogens is The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentration in the sex hormone target organs. Alteplase is Not available. bound to plasma proteins. Esterified estrogens is Approximately 95-98% of estradiol is bound loosely to albumin or tightly to sex hormone binding globulin. bound to plasma proteins. Alteplase metabolism: Alteplase is mainly metabolized by the liver. The carbohydrate and polypeptide domains of alteplase interact with hepatic glycoprotein receptors, leading to receptor-mediated endocytosis. In vivo studies suggest that alteplase follows zero-order kinetics, meaning that its metabolism is saturable at higher plasma concentrations. Esterified estrogens metabolism: Hepatic; partial metabolism via CYP3A4 enzymes; estradiol is reversibly converted to estrone and estriol; oral estradiol also undergoes enterohepatic recirculation by conjugation in the liver, followed by excretion of sulfate and glucuronide conjugates into the bile, then hydrolysis in the intestine and estrogen reabsorption. Sulfate conjugates are the primary form found in postmenopausal women. Alteplase is eliminated via In healthy volunteers, more than 80% of alteplase is eliminated through urine 18 hours after administration. Esterified estrogens is eliminated via Mainly urinary as estradiol, estrone, estriol, and their glucuronide and sulfate conjugates. The half-life of Alteplase is Alteplase has an initial half-life of less than 5 minutes in patients with acute myocardial infarction (AMI). The dominant initial plasma half-life of the 3-hour and the accelerated regimens for AMI are similar. The half-life of Esterified estrogens is Half-life varies, it is in the range 1-2 hr. The clearance of Alteplase is Alteplase has a plasma clearance between 380 and 570 mL/min. The clearance of Esterified estrogens is There is variation in the clearance rate depends on each estrogen individual:. Estradiol-17β is 580 L/day/m2. Estrone is 4050 L/day/m2. Estriol is 1110 L/day/m2. Alteplase toxicity includes Toxicity information regarding alteplase is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as risk of bleeding and thromboembolic events. Symptomatic and supportive measures are recommended. The carcinogenic potential of alteplase or its effect on fertility have not been evaluated. In vivo studies evaluating tumorigenicity and in vitro studies evaluating mutagenicity were negative. It has been estimated that the acute oral and dermal toxicity of alteplase is above 5,000 mg/kg. Esterified estrogens toxicity includes LD50 IP 325 mg/Kg (rat). LD50 IV 1740 mg/Kg (mouse). LD50 oral >5000 mg/Kg (rat). Brand names of Alteplase include Activase, Cathflo, Cathflo Activase. Brand names of Esterified estrogens include Covaryx, Menest. No synonyms are available for Alteplase. No synonyms are available for Esterified estrogens. Estrogens, esterified Estrogens,esterified Alteplase summary: It is Alteplase is a recombinant form of human tissue plasminogen activator used in the emergency treatment of myocardial infarction, ischemic stroke, and pulmonary emboli. Esterified estrogens summary: It is Esterified estrogens is a female hormone used to treat conditions related to estrogen deficiency and moderate to severe vasomotor menopausal symptoms in women. Answer: Estrogens activate the coagulation pathway via increasing plasma fibrinogen and the activity of coagulation factors such as factors VII and X. Co-administration of estrogens with anticoagulant agents may interfere with the anticoagulant actions of those agents.

Alteplase

Drug A is Ademetionine. Drug B is Carvedilol. The severity of the interaction is minor. The metabolism of Carvedilol can be decreased when combined with Ademetionine. When a CYP2E1 substrate is administered concurrently with a weak CYP2E1 inhibitor, the CYP2E1 mediated metabolism of the substrate will subsequently be reduced weakly, potentially resulting in increases in the serum concentration of the substrate. Such increased serum concentrations may also result in the increased risk, incidence, and/or severity of adverse effects associated with exposure to the given substrate as well. Ademetionine is indicated for S-Adenosylmethionine (SAMe) is used as a drug in Europe for the treatment of depression, liver disorders, fibromyalgia, and osteoarthritis. It has also been introduced into the United States market as a dietary supplement for the support of bone and joint health, as well as mood and emotional well being. Carvedilol is indicated for Carvedilol is indicated to treat mild to severe heart failure, left ventricular dysfunction after myocardial infarction with ventricular ejection fraction ≤40%, or hypertension. Ademetionine pharmacodynamics: S-adenosylmethionine is an intermediate metabolite of methionine. Its involvement in methylation assists in cellular growth and repair, maintains the phospho-bilipid layer in cell membranes. It also helps in the maintenance of the action of several hormones and neurotransmitters that affect mood. Highest concentration are found in the brain and the liver. Carvedilol pharmacodynamics: Carvedilol reduces tachycardia through beta adrenergic antagonism and lowers blood pressure through alpha-1 adrenergic antagonism. It has a long duration of action as it is generally taken once daily and has a broad therapeutic index as patients generally take 10-80mg daily. Patients taking carvedilol should not abruptly stop taking this medication as this may exacerbate coronary artery disease. The mechanism of action of Ademetionine is that it S-Adenosylmethionine (SAMe) is a natural substance present in the cells of the body. It is a direct metabolite of the essential amino acid L-methionine. SAMe plays a crucial biochemical role in the body by donating a one-carbon methyl group in a process called transmethylation. SAMe, formed from the reaction of L-methionine and adenosine triphosphate catalyzed by the enzyme S-adenosylmethionine synthetase, is the methyl-group donor in the biosynthesis of both DNA and RNA nucleic acids, phospholipids, proteins, epinephrine, melatonin, creatine and other molecules. The mechanism of action of Carvedilol is that it Carvedilol inhibits exercise induce tachycardia through its inhibition of beta adrenoceptors. Carvedilol's action on alpha-1 adrenergic receptors relaxes smooth muscle in vasculature, leading to reduced peripheral vascular resistance and an overall reduction in blood pressure. At higher doses, calcium channel blocking and antioxidant activity can also be seen. The antioxidant activity of carvedilol prevents oxidation of low density lipoprotein and its uptake into coronary circulation. Ademetionine absorption: S-Adenosylmethionine is absorbed from the small intestine following oral intake. As absorption is affected by food, it is best to take on an empty stomach. Bioavailability is low following oral intake. Carvedilol absorption: Carvedilol has a bioavailability of 25-35%. Carvedilol has a Tmax of 1 to 2 hours. Taking carvedilol with a meal increases Tmax without increasing AUC. Carvedilol doses of 50mg lead to a Cmax of 122-262µg/L and an AUC of 717-1600µg/L*h. Carvedilol doses of 25mg lead to a Cmax of 24-151µg/L and an AUC of 272-947µg/L*h. Carvedilol doses of 12. 5mg lead to a Cmax of 58-69µg/L and an AUC of 208-225µg/L*h. No volume of distribution information is available for Ademetionine. The volume of distribution of Carvedilol is Carvedilol has a volume of distribution of 1. 5-2L/kg or 115L. No protein binding information is available for Ademetionine. Carvedilol is Carvedilol is 98% protein bound in plasma. 95% of carvedilol is bound to serum albumin. bound to plasma proteins. Ademetionine metabolism: Significant first-pass metabolism in the liver. Approximately 50% of S-Adenosylmethionine (SAMe) is metabolized in the liver. SAMe is metabolized to S-adenosylhomocysteine, which is then metabolized to homocysteine. Homocysteine can either be metabolized to cystathionine and then cysteine or to methionine. The cofactor in the metabolism of homocysteine to cysteine is vitamin B6. Cofactors for the metabolism of homocysteine to methionine are folic acid, vitamin B12 and betaine. Carvedilol metabolism: Carvedilol can be hydroxlated at the 1 position by CYP2D6, CYP1A2, or CYP1A1 to form 1-hydroxypheylcarvedilol; at the 4 position by CYP2D6, CYP2E1, CYP2C9, or CYP3A4 to form 4'-hydroxyphenylcarvedilol; at the 5 position by CYP2D6, CYP2C9, or CYP3A4 to form 5'-hydroxyphenylcarvedilol; and at the 8 position by CYP1A2, CYP3A4, and CYP1A1 to form 8-hydroxycarbazolylcarvedilol. Carvedilol can also be demethylated by CYP2C9, CYP2D6, CYP1A2, or CYP2E1 to form O-desmethylcarvedilol. Carvedilol and its metabolites may undergo further sulfate conjugation or glucuronidation before elimination. Carvedilol can be O-glucuronidated by UGT1A1, UGT2B4, and UGT2B7 to form carvedilol glucuronide. Ademetionine is eliminated via No route of elimination available. Carvedilol is eliminated via 16% of carvedilol is excreted in the urine with <2% excreted as unmetabolized drug. Carvedilol is primarily excreted in the bile and feces. The half-life of Ademetionine is No half-life available. The half-life of Carvedilol is The half life of carvedilol is between 7-10 hours, though significantly shorter half lives have also been reported. No clearance information is available for Ademetionine. The clearance of Carvedilol is The plasma clearance of carvedilol has been reported as 0. 52L/kg or 500-700mL/min. Ademetionine toxicity includes Irritating to mucus membranes and upper respiratory tract. Can cause CNS depression. Carvedilol toxicity includes Patients experiencing an overdose may present with hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Patients should remain in a supine position and may be given atropine for bradycardia and glucagon followed by sympathomimetics to support cardiovascular function. Brand names of Ademetionine include No brand names available. Brand names of Carvedilol include Coreg. No synonyms are available for Ademetionine. AdoMet L-S-Adenosylmethionine S-Adenosylmethionine SAM-e SAMe No synonyms are available for Carvedilol. Carvédilol Carvedilolum Ademetionine summary: It is No summary available. Carvedilol summary: It is Carvedilol is a non selective beta-adrenergic antagonist used to treat mild to severe chronic heart failure, hypertension, and left ventricular dysfunction following myocardial infarction in clinically stable patients. Answer: When a CYP2E1 substrate is administered concurrently with a weak CYP2E1 inhibitor, the CYP2E1 mediated metabolism of the substrate will subsequently be reduced weakly, potentially resulting in increases in the serum concentration of the substrate. Such increased serum concentrations may also result in the increased risk, incidence, and/or severity of adverse effects associated with exposure to the given substrate as well.

Ademetionine

Drug A is Bupivacaine. Drug B is Buprenorphine. The severity of the interaction is moderate. Bupivacaine may increase the central nervous system depressant (CNS depressant) activities of Buprenorphine. Buprenorphine is a central nervous system depressant. Administering other drugs within the central nervous system (CNS) depressant class of drugs may potentiate these effects. Significant respiratory depression and death have been reported in association with buprenorphine, especially when taken by the intravenous (IV) route in combination with other CNS depressants. Bupivacaine is indicated for As an implant, bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. Bupivacaine, in liposome suspension, is indicated in patients aged 6 years and older for single-dose infiltration to produce postsurgical local analgesia. In adults, it is also indicated to produce regional analgesia via an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Bupivicaine, in combination with meloxicam, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided. Bupivacaine, alone or in combination with epinephrine, is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations are recommended for each type of block indicated to produce local or regional anesthesia or analgesia. Finally, its use is not indicated in all blocks given clinically significant risks associated with use. Buprenorphine is indicated for Buprenorphine is available in different formulations, such as sublingual tablets, buccal films, transdermal films, and injections, alone or in combination with naloxone. The buccal film, intramuscular or intravenous injection, and transdermal formulation are indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. The extended-release subcutaneous injections of buprenorphine are indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. Injections are part of a complete treatment plan that includes counselling and psychosocial support. Sublingual tablets and buccal films, in combination with naloxone, are indicated for the maintenance treatment of opioid dependence as part of a complete treatment plan that includes counselling and psychosocial support. Bupivacaine pharmacodynamics: Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. Buprenorphine pharmacodynamics: Buprenorphine interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, buprenorphine exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Buprenorphine depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Dependence Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. [F4718] Withdrawal Abrupt discontinuation of treatment is not recommended as it may result in an opioid withdrawal syndrome that may be delayed in onset. Signs and symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. [F4718] Risk of Respiratory and Central Nervous System (CNS) Depression and Overdose Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant, including alcohol. Use buprenorphine and naloxone sublingual tablets with caution in patients with compromised respiratory function (e. g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression). Risk of Overdose in Opioid Naïve Patients There have been reported deaths of opioid-naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine and naloxone sublingual tablets are not appropriate as an analgesic in opioid-naïve patients. Precipitation of Opioid Withdrawal Signs and Symptoms If buprenorphine is started in opioid-dependent individuals, it will displace the other opioids and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms. Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Because it contains naloxone, buprenorphine and naloxone sublingual tablets are also highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Gastrointestinal Effects Buprenorphine and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and should be administered with caution to patients with dysfunction of the biliary tract. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Use in Patients With Impaired Hepatic Function Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. The doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. However, buprenorphine/naloxone products are not recommended for initiation of (treatment induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy. Risk of Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, buprenorphine and naloxone sublingual tablets may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated. Orthostatic Hypotension Like other opioids, buprenorphine and naloxone sublingual tablets may produce orthostatic hypotension in ambulatory patients. Elevation of Cerebrospinal Fluid Pressure Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation. Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract. The mechanism of action of Bupivacaine is that it Like lidocaine, bupivacaine is an amide local anesthetic that provides local anesthesia through blockade of nerve impulse generation and conduction. These impulses, also known as action potentials, critically depend on membrane depolarization produced by the influx of sodium ions into the neuron through voltage-gated sodium channels. Bupivacaine crosses the neuronal membrane and exerts its anesthetic action through blockade of these channels at the intracellular portion of their pore-forming transmembrane segments. The block is use-dependent, where repetitive or prolonged depolarization increases sodium channel blockade. Without sodium ions passing through the channel’s pore, bupivacaine stabilizes the membrane at rest and therefore prevents neurotransmission. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. While it is well-established that the main action of bupivacaine is through sodium channel block, additional analgesic effects of bupivacaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia. The mechanism of action of Buprenorphine is that it Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. It demonstrates a high affinity for the mu-opioid receptor but has lower intrinsic activity compared to other full mu-opioid agonists such as heroin, oxycodone, or methadone. This means that buprenorphine preferentially binds the opioid receptor and displaces lower affinity opioids without activating the receptor to a comparable degree. Clinically, this results in a slow onset of action and a clinical phenomenon known as the "ceiling effect" where once a certain dose is reached buprenorphine's effects plateau. This effect can be beneficial, however, as dose-related side effects such as respiratory depression, sedation, and intoxication also plateau at around 32mg, resulting in a lower risk of overdose compared to methadone and other full agonist opioids. It also means that opioid-dependent patients do not experience sedation or euphoria at the same rate that they might experience with more potent opioids, improving quality of life for patients with severe pain and reducing the reinforcing effects of opioids which can lead to drug-seeking behaviours. Buprenorphine's high affinity, but low intrinsic activity for the mu-opioid receptor also means that if it is started in opioid-dependent individuals, it will displace the other opioids without creating an equal opioid effect and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms (i. e. anxiety, restlessness, gastrointestinal distress, diaphoresis, intense drug cravings, and tachycardia). Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Buprenorphine is commercially available as the brand name product Suboxone which is formulated in a 4:1 fixed-dose combination product along with naloxone, a non-selective competitive opioid receptor antagonist. Combination of an opioid agonist with an opioid antagonist may seem counterintuitive, however this combination with naloxone is intended to reduce the abuse potential of Suboxone, as naloxone is poorly absorbed by the oral route (and has no effect when taken orally), but would reverse the opioid agonist effects of buprenorphine if injected intravenously. Bupivacaine absorption: Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a Cmax of 54 ± 33 ng/mL, a median Tmax of 3 h, and an AUC ∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 ng*h/mL. Buprenorphine absorption: Bioavailablity of buprenorphine/naloxone is very high following intravenous or subcutaneous administration, lower by the sublingual or buccal route, and very low when administered by the oral route. It is therefore provided as a sublingual tablet that is absorbed from the oral mucosa directly into systemic circulation. Clinical pharmacokinetic studies found that there was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional. Buprenorphine combination with naloxone (2mg/0. 5mg) provided in sublingual tablets demonstrated a Cmax of 0. 780 ng/mL with a Tmax of 1. 50 hr and AUC of 7. 651 ng. hr/mL. Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine. No volume of distribution information is available for Bupivacaine. The volume of distribution of Buprenorphine is Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. It is able to cross into the placenta and breast milk. Bupivacaine is Bupivacaine is ~95% protein bound. bound to plasma proteins. Buprenorphine is Buprenorphine is approximately 96% protein-bound, primarily to alpha- and beta-globulin. bound to plasma proteins. Bupivacaine metabolism: Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4. Buprenorphine metabolism: Buprenorphine is metabolized to norbuprenorphine via Cytochrome P450 3A4/3A5-mediated N-dealkylation. Buprenorphine and norbuprenorphine both also undergo glucuronidation to the inactive metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, respectively. While norbuprenorphine has been found to bind to opioid receptors in-vitro, brain concentrations are very low which suggests that it does not contribute to the clinical effects of buprenorphine. Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group. Bupivacaine is eliminated via Only 6% of bupivacaine is excreted unchanged in the urine. Buprenorphine is eliminated via Buprenorphine, like morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine). The overall mean elimination half-life of buprenorphine in plasma ranges from 31 to 42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter. The half-life of Bupivacaine is 2. 7 hours in adults and 8. 1 hours in neonates. Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 hours, depending on dose and application site. The half-life of Buprenorphine is Buprenorphine demonstrates slow dissociation kinetics (~166 min), which contributes to its long duration of action and allows for once-daily or even every-second-day dosing. In clinical trial studies, the half-life of sublingually administered buprenorphine/naloxone 2mg/0. 5mg was found to be 30. 75 hours. No clearance information is available for Bupivacaine. The clearance of Buprenorphine is Clearance may be higher in children than in adults. Plasma clearance rate, IV administration, anaesthetized patients = 901. 2 ± 39. 7 mL/min; Plasma clearance rate, IV administration, healthy subjects = 1042 - 1280 mL/min. Bupivacaine toxicity includes The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4. 4 mg/kg with mean arterial plasma concentration of 4. 5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. Buprenorphine toxicity includes Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression and death. Brand names of Bupivacaine include Exparel, Kenalog, Marbeta, Marcaine, Marcaine With Epinephrine, Marvona Suik, P-Care M, P-Care MG, P-care, Posimir, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Sensorcaine, Sensorcaine With Epinephrine, Vivacaine, Xaracoll, Zynrelef. Brand names of Buprenorphine include Belbuca, Brixadi, Buprenex, Buprenorphine, Butrans, Sublocade, Suboxone, Subutex, Zubsolv. No synonyms are available for Bupivacaine. Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine No synonyms are available for Buprenorphine. Buprenorfina Buprenorphine Buprenorphinum Bupivacaine summary: It is Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures. Buprenorphine summary: It is Buprenorphine is a partial opioid agonist used for management of severe pain that is not responsive to alternative treatments. Also used for maintenance treatment of opioid addiction. Answer: Buprenorphine is a central nervous system depressant. Administering other drugs within the central nervous system (CNS) depressant class of drugs may potentiate these effects. Significant respiratory depression and death have been reported in association with buprenorphine, especially when taken by the intravenous (IV) route in combination with other CNS depressants.

Bupivacaine

Drug A is Denosumab. Drug B is Ruxolitinib. The severity of the interaction is moderate. The risk or severity of adverse effects can be increased when Denosumab is combined with Ruxolitinib. The coadministration of denosumab with immunosuppressive agents poses a high risk of serious infection than with denosumab alone. 1,2,3 Denosumab is indicated for Denosumab under the brand name Prolia is indicated as a treatment for osteoporosis in menopausal women or men and glucocorticoid-induced osteoporosis in men and women at high risk of fracture. It is also used to increase bone mass in men at high risk for fractures receiving androgen deprivation therapy for nonmetastatic prostate cancer or women at high risk for fractures receiving adjuvant aromatase inhibitor therapy for breast cancer. Denosumab under the brand name Xgeva is indicated to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors and to treat giant cell tumors of bone in adults and skeletally mature adolescents and hypercalcemia of malignancy refractory to bisphosphonate therapy. Ruxolitinib is indicated for Ruxolitinib is indicated for the treatment of the following conditions: intermediate or high-risk myelofibrosis (MF), including prima1y MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults. It is also used to treat disease-related splenomegaly or symptoms in adult patients with these conditions. polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea. steroid-refracto1y acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older. chronic GVHD in patients aged 12 years and older who have failed one or two lines of systemic therapy. Topical ruxolitinib is indicated for: the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. the treatment of non-segmental vitiligo in adult and pediatric patients 12 years of age and older. Denosumab pharmacodynamics: In clinical studies, treatment with 60 mg of denosumab resulted in a reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0. 049 ng/mL) in 39% to 68% of patients 1 to 3 months after dosing of denosumab. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of denosumab on bone remodelling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by denosumab was similar to that observed in patients initiating denosumab treatment. Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i. e., osteocalcin and procollagen type 1 N-terminal peptide [P1NP]) were observed starting 1 month after the first dose of denosumab. After discontinuation of denosumab therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months. In patients with breast cancer and bone metastases, the median reduction in urinary N-terminal telopeptide corrected for creatinine (uNTx/Cr) was 82% within 1 week following initiation of denosumab 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 denosumab-treated patients. In a phase 3 study of patients with newly diagnosed multiple myeloma who received subcutaneous doses of denosumab 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing. Ruxolitinib pharmacodynamics: Ruxolitinib is an antineoplastic agent that inhibits cell proliferation, induces apoptosis of malignant cells, and reduces pro-inflammatory cytokine plasma levels by inhibiting JAK-induced phosphorylation of signal transducer and activator of transcription (STAT). Inhibition of STAT3 phosphorylation, which is used as a marker of JAK activity, by ruxolitinib is achieved at two hours after dosing which returned to near baseline by 10 hours in patients with myelofibrosis and polycythemia vera. In clinical trials, ruxolitinib reduced splenomegaly and improved symptoms of myelofibrosis. In a mouse model of myeloproliferative neoplasms, administration of ruxolitinib was associated with prolonged survival. Ruxolitinib inhibits both mutant and wild-type JAK2; however, JAK2V617F mutation, which is often seen in approximately 50% of patients with myelofibrosis, was shown to reduce ruxolitinib sensitivity, which may also be associated with possible resistance to JAK inhibitor treatment. The mechanism of action of Denosumab is that it Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. The mechanism of action of Ruxolitinib is that it The Janus kinase (JAK) family of protein tyrosine kinases comprises JAK1, JAK2, JAK3, and non-receptor tyrosine kinase 2 (TYK2). JAKs play a pivotal role in intracellular signalling pathways of various cytokines and growth factors essential to hematopoiesis, such as interleukin, erythropoietin, and thrombopoietin. JAKs have diverse functions: JAK1 and JAK3 promote lymphocyte differentiation, survival, and function, while JAK2 promotes signal transduction of erythropoietin and thrombopoietin. JAKs are in close proximity to the cytokine and growth factor receptor’s cytoplasmic region. Upon binding of cytokines and growth factors, JAKs are activated, undergoing cross-phosphorylation and tyrosine phosphorylation. This process also reveals selective binding sites for STATs, which are DNA-binding proteins that also bind to the cytoplasmic region of cytokine or growth factor receptors. Activated JAKs and STATs translocate to the nucleus as transcription factors to regulate gene expression of pro-inflammatory cytokines such as IL-6, IL-10, and nuclear factor κB (NF-κB). They also activate downstream pathways that promote erythroid, myeloid, and megakaryocytic development. The molecular pathogenesis of myeloproliferative neoplasms is not fully understood; however, JAK2 is constitutively activated and the JAK-STAT signalling pathway becomes deregulated and aberrant. Ruxolitinib is a selective and potent inhibitor of JAK2 and JAK1, with some affinity against JAK3 and TYK2. Anticancer effects of ruxolitinib are attributed to its inhibition of JAKs and JAK-mediated phosphorylation of STAT3. By downregulating the JAK-STAT pathway, ruxolitinib inhibits myeloproliferation and suppresses the plasma levels of pro-inflammatory cytokines such as IL-6 and TNF-α. Activated JAKs are also implicated in graft-versus-host-disease (GVHD), which is a severe immune complication of allogeneic hematopoietic cell transplantation GVHD is associated with significant morbidity and mortality, especially for patients who do not respond well to corticosteroid therapy. Activated JAKS stimulate T-effector cell responses, leading to increased proliferation of effector T cells and heightened production of pro-inflammatory cytokines. By blocking JAK1 and JAk2, ruxolitinib inhibits donor T-cell expansion and suppresses pro-inflammatory responses. Denosumab absorption: In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered denosumab dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (Cmax ) was 6. 75 mcg/mL (standard deviation [SD] = 1. 89 mcg/mL). The median time to maximum denosumab concentration (Tmax ) was 10 days (range: 3 to 21 days). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg⋅day/mL (SD = 101 mcg⋅day/mL. No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months. Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years). After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) Cmax values in the serum and seminal fluid samples were 6170 (± 2070) and 100 (± 81. 9) ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels. The median (range) Tmax values in the serum and seminal fluid samples were 8. 0 (7. 9 to 21) and 21 (8. 0 to 49) days, respectively. Among the subjects, the highest denosumab concentration in the seminal fluid was 301 ng/mL at 22 days post-dose. On the first day of measurement (10 days post-dose), nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post-dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) seminal fluid concentration of 21. 1 (± 36. 5) ng/mL across all subjects (n = 12). In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach a steady state by month 6. In patients with giant cell tumor of bone, after administration of subcutaneous doses of 120 mg once every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day 8, 15, and one month after the first dose were 19. 0 (± 24. 1), 31. 6 (± 27. 3), 36. 4 (± 20. 6) mcg/mL,. respectively. Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23. 4 (± 12. 1) mcg/mL. Ruxolitinib absorption: Following oral administration, ruxolitinib undergoes rapid absorption and the peak concentrations are reached within one hour after administration. Over a single-dose range of 5 mg to 200 mg, the mean maximal plasma concentration (Cmax ) increases proportionally. Cmax ranged from 205 nM to 7100 nM and AUC ranged from 862 nM x hr to 30700 nM x hr. Tmax ranges from one to two hours following oral administration. Oral bioavailability is at least 95%. The volume of distribution of Denosumab is The central volume of distribution and volume of distribution at steady-state were calculated to be 2. 49 L/66 kg and 3. 5-7 L respectively. The volume of distribution of Ruxolitinib is The mean volume of distribution (%coefficient of variation) at steady-state is 72 L (29%) in patients with myelofibrosis and 75 L (23%) in patients with polycythemia vera. It is not known whether ruxolitinib crosses the blood-brain barrier. Denosumab is No information is available on the protein binding of denosumab. bound to plasma proteins. Ruxolitinib is Ruxolitinib is approximately 97% bound to plasma proteins, mostly to albumin. bound to plasma proteins. Denosumab metabolism: No information is available on the metabolism of denosumab. Ruxolitinib metabolism: More than 99% of orally-administered ruxolitinib undergoes metabolism mediated by CYP3A4 and, to a lesser extent, CYP2C9. The major circulating metabolites in human plasma were M18 formed by 2-hydroxylation, and M16 and M27 (stereoisomers) formed by 3-hydroxylation. Other identified metabolites include M9 and M49, which are formed by hydroxylation and ketone formation. Not all metabolite structures are fully characterized and it is speculated that many metabolites exist in stereoisomers. Metabolites of ruxolitinib retain inhibitory activity against JAK1 and JAk2 to a lesser degree than the parent drug. Denosumab is eliminated via As an antibody, denosumab is likely cleared by the reticuloendothelial system with minimal renal filtration and excretion. Ruxolitinib is eliminated via Following oral administration of a single radiolabeled dose of ruxolitinib, the drug was mainly eliminated through metabolism. About 74% of the total dose was excreted in urine and 22% was excreted in feces, mostly in the form of hydroxyl and oxo metabolites of ruxolitinib. The unchanged parent drug accounted for less than 1% of the excreted total radioactivity. The half-life of Denosumab is After Cmax, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25. 4 days (SD = 8. 5 days; n = 46). The half-life of Ruxolitinib is The mean elimination half-life of ruxolitinib is approximately 3 hours and the mean half-life of its metabolites is approximately 5. 8 hours. The clearance of Denosumab is No information is available on the clearance of denosumab. The clearance of Ruxolitinib is Ruxolitinib clearance (% coefficient of variation) is 17. 7 L/h in women and 22. 1 L/h in men with myelofibrosis. Drug clearance was 12. 7 L/h (42%) in patients with polycythemia vera and 11. 9 L/h (43%) in patients with acute graft-versus-host disease. Denosumab toxicity includes Denosumab is contraindicated for use in pregnant women because it may cause harm to a fetus. There are insufficient data with denosumab use in pregnant women to inform any drug-associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes,. abnormal bone growth, and decreased neonatal growth. In clinical trials, hypercalcemia has been reported in pediatric patients with osteogenesis imperfect treated with denosumab products, including Prolia. Some cases required hospitalization and were complicated by acute renal injury. Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years. The carcinogenic and genotoxic potential of denosumab has not been evaluated in long-term animal studies. Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg). Ruxolitinib toxicity includes The oral LD 50 was 250 mg/kg. Single doses of ruxolitinib up to 200 mg were tolerated well. Higher doses than recommended repeat doses are associated with myelosuppression, including leukopenia, anemia, and thrombocytopenia. There is no known antidote for overdoses with ruxolitinib: it is recommended that patients are given appropriate supportive treatment. Hemodialysis is not expected to enhance the elimination of ruxolitinib. Brand names of Denosumab include Prolia, Xgeva. Brand names of Ruxolitinib include Jakafi, Jakavi, Opzelura. No synonyms are available for Denosumab. No synonyms are available for Ruxolitinib. Denosumab summary: It is Denosumab is a RANK ligand (RANKL) inhibitor used for the management of osteoporosis in patients at high risk for bone fractures. Ruxolitinib summary: It is Ruxolitinib is a kinase inhibitor used to treat various types of myelofibrosis, polycythemia vera in patients who have not responded to or cannot tolerate hydroxyurea, and to treat graft-versus-host disease in cases that are refractory to steroid treatment. Answer: The coadministration of denosumab with immunosuppressive agents poses a high risk of serious infection than with denosumab alone.

Denosumab

Drug A is Brentuximab vedotin. Drug B is Midazolam. The severity of the interaction is moderate. The serum concentration of Midazolam can be increased when it is combined with Brentuximab vedotin. Midazolam is metabolized by CYP3A4. 3 Pharmacokinetic interactions with CYP3A4 inhibitors are more pronounced for oral as compared to oromucosal or parenteral midazolam as CYP3A4 enzymes are also present in the upper gastro-intestinal tract. The magnitude of interaction with oral midazolam may be greater due to inhibition of CYP3A in both the intestine and liver, and the resultant decrease in first-pass metabolism of midazolam. Conversely, after oromucosal administration, only systemic clearance will be affected. After a single dose of oromucosal midazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. Furthermore, after a single dose of i. v. midazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. However, after prolonged dosing of midazolam, both the magnitude and duration of effect will be increased in the presence of CYP3A4 inhibition. Hence, careful monitoring of the clinical effects and vital signs is recommended during the use of midazolam with a CYP3A4 inhibitor even after a single dose. Brentuximab vedotin is indicated for Brentuximab vedotin is indicated in adult patients for the treatment of previously untreated stage III or IV classical Hodgkin's lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine. It is also indicated for the treatment of cHL post-autologous hematopoietic stem cell transplantation (auto-HSCT) in patients at high risk of relapse or progression. Finally, it may be used in the treatment of adult patients with cHL who have previously failed either auto-HSCT or at least two prior multi-agent chemotherapy regimens if they are not candidates for auto-HSCT. Brentuximab vedotin is additionally indicated in the treatment of previously untreated systemic anaplastic large cell lymphoma (sALCL), or other CD30-expressing peripheral T-cell lymphomas (PTCL), in combination with cyclophosphamide, doxorubicin, and prednisone. It may also be used as monotherapy in sALCL after therapeutic failure of a least one prior multi-agent chemotherapy regimen. Brentuximab vedotin is also indicated in the treatment of primary cutaneous large anaplastic large cell lymphoma, or CD30-expressing mycosis fungoides, who have received prior systemic therapy. Midazolam is indicated for Midazolam has different indications depending on its formulation by the FDA. Nasal For the nasal spray formulation, midazolam is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i. e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older. Intravenous For the intravenous injection formulation, midazolam is indicated as an agent for sedation/anxiolysis/amnesia and prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants. The sedative, anxiolytic and amnestic use of midazolam can also be employed pre-operatively. It can also be indicated for induction of general anesthesia, before administration of other anesthetic agents or as a component of intravenous supplementation of nitrous oxide and oxygen for a balanced anesthesia. A relatively narrower dose range of midazolam and a shorter period of induction can be achieved if midazolam is combined with narcotic premedication. Finally, midazolam can be indicated as a continous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting. Intramuscular For the intramusuclar injection formulation, midazolam is indicated for preoperative sedation/anxiolysis/amnesia or for treatment of status epilepticus in adults. Oral Midazolam syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia. It is only approved in monitored settings only and not for chronic or home use. In Europe, a buccal formulation of midazolam is also approved for the treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to < 18 years). For infants between 3-6 months of age treatment should be in a hospital setting where monitoring is possible and resuscitation equipment is available. Brentuximab vedotin pharmacodynamics: Brentuximab vedotin causes apoptosis of tumor cells by preventing cell cycle progression of the G2 to M phase through disruption of the cytosolic microtuble network, thus preventing tumor growth and proliferation. Hodgkin lymphoma (HL) is characterized by malignant Reed-Sternberg cells which express CD30, a marker of large cell lymphoma. Until March 2018, USA National Comprehensive Cancer Network guidelines for patients with advanced HL (stage III/IV disease) recommend treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), or escalated bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) as first-line regimens. ABVD appears to be as effective, with fewer side effects, as escalated BEACOPP. Escalated BEACOPP leads to a greater progression-free survival but no difference in overall survival. Recent progress in technology has enabled a new shift to cancer therapy targeting specific molecules. Brentuximab vedotin, a CD30-directed antibody conjugate, selectively targets malignant HL cells. The effect of Brentuximab vedotin (1. 8 mg/kg) on the QTc interval was studied in an open-label, single-group study in 46 patients diagnosed with CD30-expressing hematologic malignancies. Ingestion of brentuximab vedotin did not prolong the mean cardiac QTc interval >10 ms from baseline levels. Smaller increases in the mean QTc interval (<10 ms) cannot be ruled out because this study did not include a placebo arm and a positive control arm. Midazolam pharmacodynamics: General effects Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant. Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepine drugs, include sedative, anxiolytic, amnestic, muscle relaxant, as well as hypnotic activities. Benzodiazepines enhance the inhibitory action of the amino acid neurotransmitter gamma-aminobutyric acid (GABA). Receptors for GABA are targeted by many important drugs that affect GABA function and are commonly used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, and aggressive behavior. Sedation and memory The onset of sedation after intramuscular administration in adults is 15 minutes, with maximal sedation occurring 30-60 minutes after injection. In one study of adults, when tested the following day, 73% of the patients who were administered midazolam intramuscularly had no recollection of memory cards shown 30 minutes following drug administration; 40% had no recollection of the memory cards shown 60 minutes after drug administration. Onset time of sedative effects in pediatric patients begins within 5 minutes and peaks at 15-30 minutes depending upon the dose administered. In the pediatric population, up to 85% had no memory of pictures shown after receiving intramuscular midazolam compared to 5% of the placebo control group. Sedation in both adult and pediatric patients is reached within 3 to 5 minutes post intravenous (IV) injection. The time of onset is affected by the dose administered and the simultaneous administration of narcotic pre-medication. Seventy-one (71%) percent of the adult patients in clinical endoscopy studies had no memory of insertion of the endoscope; 82% of the patients had no memory of withdrawal of the endoscope. Anesthesia induction When midazolam is administered intravenously (IV) for anesthetic induction, induction of anesthesia occurs in about 1. 5 minutes when narcotic pre-medication has been given and in 2 to 2. 5 minutes without narcotic pre-medication/ other sedative pre-medication. Impairment in a memory test was observed in 90% of the patients. The mechanism of action of Brentuximab vedotin is that it Brentuximab vedotin is composed of 3 parts: a chimeric human-murine IgG1 that selectively targets CD30, monomethyl auristatin E (MMAE), which is a microtubule-disrupting agent, and a protease-susceptible linker that links the antibody and MMAE. The IgG1 antibody enables Brentuximab vedotin to target tumor cells expressing CD30 on their surface. Following this Brentuximab vedotin enters the cell. Once inside, the linker is cleaved releasing MMAE which binds disrupts the microtubule network. The antibody component of this drug is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule-disrupting particle. MMAE is covalently attached to the antibody by a linker. Data suggest that the anticancer activity of Adcertris is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the subsequent release of MMAE by proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptotis of the malignant cells. The mechanism of action of Midazolam is that it The actions of benzodiazepines such as midazolam are mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which is one of the major inhibitory neurotransmitters in the central nervous system. Benzodiazepines increase the activity of GABA, thereby producing a sedating effect, relaxing skeletal muscles, and inducing sleep, anesthesia, and amnesia. Benzodiazepines bind to the benzodiazepine site on GABA-A receptors, which potentiates the effects of GABA by increasing the frequency of chloride channel opening. These receptors have been identified in different body tissues including the heart and skeletal muscle, although mainly appear to be present in the central nervous system. Brentuximab vedotin absorption: Steady-state of the ADC is achieved within 21 days with every 3-week dosing of Adcetris. Minimal to no accumulation of ADC is observed with multiple doses at the every 3-week schedule. The time to maximum concentration for MMAE ranges from approximately 1 to 3 days. Similar to the ADC, steady-state of MMAE is achieved within 21 days with every 3-week dosing of Adcetris. MMAE exposures decrease with continued administration of Adcetris with about 50% to 80% of the exposure of the first dose being observed at future doses. The AUC of MMAE was measured to be approximately 2. 2-fold higher in patients with hepatic impairment in comparison with patients with normal hepatic function. Midazolam absorption: Intramuscular Following IM administration of a single 10 mg midazolam dose to healthy subjects, midazolam was absorbed with median Tmax (range) of 0. 5 (0. 25 to 0. 5) hours; midazolam's mean (±SD) Cmax and AUC 0-∞ were 113. 9 (±30. 9) ng/mL and 402. 7 (±97. 0) ng∙h/mL, respectively. Rectal After rectal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes. The absolute bioavailability is approximately 50%. Intranasal Administration Following the nasal administration of a single 5 mg midazolam dose to healthy adults, midazolam was absorbed with a median Tmax (range) of 17. 3 (7. 8 to 28. 2) minutes; midazolam's mean (±SD) Cmax and AUC 0-∞ were 54. 7 (±30. 4) ng/mL and 126. 2 (±59) ng∙h/mL, respectively. The mean absolute bioavailability is approximately 44%. Oral In pediatric patients from 6 months to <16 years old, the mean Tmax values across dose groups (0. 25, 0. 5, and 1. 0 mg/kg) range from 0. 17 to 2. 65 hours. Midazolam also exhibits linear pharmacokinetics within this dose range (up to a maximum dose of 40 mg). Linearity was also demonstrated across the doses within the age group of 2 years to <12 years having 18 patients at each of the three doses. Due to first-pass metabolism, only 40-50% of the administered oral dose reaches the circulation. The absolute bioavailability of midazolam is about 36%, which is not affected by pediatric age or weight. Cmax and AUC 0-∞ were also calculated to range from 28 to 201 ng/mL and 67. 6 to 821 ng∙h/mL respectively. Buccal After oromucosal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes in children. The absolute bioavailability of oromucosal midazolam is about 75% in adults. The bioavailability of oromucosal midazolam has been estimated at 87% in children with severe malaria and convulsions. Cmax and AUC 0-∞ were also calculated to range from 87 to 148 ng/mL and 168 to 254 ng∙h/mL respectively. The volume of distribution of Brentuximab vedotin is MMAE is unlikely to displace or to be displaced by highly protein-bound drugs. In vitro studies show that MMAE is a substrate of P-gp and was not a potent inhibitor of P-gp. The volume of distribution of Midazolam is Female gender, old age, and obesity may increase the volume of distribution. Midazolam may also cross the placenta and has been detected in human milk and cerebrospinal fluid. Intravenous administration In pediatric patients (6 months to <16 years) receiving 0. 15 mg/kg IV midazolam, the mean steady-state volume of distribution ranged from 1. 24 to 2. 02 L/kg. For healthy adult patients, the volume of distribution determined from six single-dose pharmacokinetic studies ranged from 1. 0 to 3. 1 L/kg. Intramuscular administration The mean (±SD) apparent volume of distribution (Vz/F) of midazolam following a single IM dose of 10 mg midazolam was 2117 (±845. 1) mL/kg in healthy subjects. Intranasal The estimated total volume of distribution of midazolam is 226. 5 L. Buccal The steady-state volume of distribution following oromucosal administration is estimated to be 5. 3 l/kg. Brentuximab vedotin is In vitro, the binding of MMAE to human plasma proteins is in the range of 68–82%. bound to plasma proteins. Midazolam is In adults and pediatric patients, midazolam is approximately 97% bound to plasma protein, principally albumin. In healthy volunteers, 1-hydroxy midazolam is bound to the extent of 89%. bound to plasma proteins. Brentuximab vedotin metabolism: Data in both animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes. Midazolam metabolism: In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by the cytochrome P450-3A4 (CYP3A4). This enzyme is present in gastrointestinal tract mucosa, as well as in the liver. The 1-hydroxy-midazolam (also termed alpha-hydroxymidazolam) metabolite comprises 60% to 70% of the biotransformation products of midazolam, while 4-hydroxy-midazolam constitutes 5% or less. Small amounts of a dihydroxy derivative have also been detected, but not quantified. Midazolam also undergoes N-glucuronidation via UGT1A4 after the process of hepatic oxidation by cytochrome enzymes. Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxymidazolam is at least as potent as the parent compound, and may contribute to the net pharmacologic activity of midazolam. In vitro studies have demonstrated that the affinities of 1- and 4-hydroxy-midazolam for the benzodiazepine receptor are approximately 20% and 7%, respectively, relative to midazolam. Brentuximab vedotin is eliminated via This drug appears follow metabolite kinetics, with the elimination of appearing to be limited by its rate of release from the antibody-drug conjugate (ADC). An excretion study was done in patients receiving a dose of 1. 8 mg/kg of Adcetris. About 24% of the total MMAE ingested as part of the ADC during an ADCETRIS infusion was recovered in both urine and feces over a 7-day time frame. Of the recovered MMAE, approximately 72% was found in the feces and the majority of the excreted MMAE was excreted as unchanged drug. Midazolam is eliminated via The α-hydroxymidazolam glucuronide conjugate of midazolam is excreted in the urine. No significant amount of parent drug or metabolites is found in urine before beta-glucuronidase and sulfatase deconjugation, suggesting that the urinary metabolites are excreted mainly as conjugates. The amount of midazolam excreted unchanged in the urine when given intravenously is less than 0. 5%. 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate. The principal urinary excretion. products are glucuronide conjugates of hydroxylated derivatives. Plasma clearance of midazolam is higher in patients that remain in the supine position, because of a 40-60 percent increase in hepatic blood flow during supination. Pregnancy may also increase the metabolism of midazolam. The half-life of Brentuximab vedotin is The terminal half-life is approximately 4-6 days. The half-life of Midazolam is Intravenous:. Six single-dose pharmacokinetic studies involving healthy adults yield an elimination half-life of 1. 8 to 6. 4 hours (mean of approximately 3 hours). Intramuscular Following IM administration of 10 mg midazolam, the mean (±SD) elimination half-life of midazolam was 4. 2 (±1. 87) hours. Intranasal Following the administration of NAYZILAM in clinical trials, median midazolam and 1-hydroxy-midazolam elimination half-lives ranged from 2. 1 to 6. 2 hours and 2. 7 to 7. 2 hours, respectively, independent of dose. Oral The mean elimination half-life of midazolam ranged from 2. 2 to 6. 8 hours following single oral doses of 0. 25, 0. 5, and 1. 0 mg/kg of midazolam HCl syrup. * Buccal The initial and terminal elimination half-lives are 27 and 204 minutes, respectively. The clearance of Brentuximab vedotin is The liver is the primary route of clearance for MMAE. The pharmacokinetics and safety of Brentuximab vedotin and MMAE were examined after the administration of 1. 2 mg/kg of Adcetris to patients with mild, moderate, and severe hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ≥Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function. It is recommended to avoid use in patients with severe renal impairment (CrCl <30mL/min). The clearance of Midazolam is Intramuscular Following IM administration of 10 mg midazolam, the apparent total body clearance (CL/F) of midazolam was 367. 3 (±73. 5) mL/hr/kg. Intravenous: Six single-dose pharmacokinetic studies involving healthy adults yield a total clearance (Cl) of 0. 25 to 0. 54 L/hr/kg. Intranasal Midazolam clearance was calculated to be 1. 9 mL/min/kg Oral Following a group of patients receiving the 0. 15 mg/kg IV dose, the mean total clearance ranged from 9. 3 to 11. 0 mL/min/kg. * Buccal Plasma clearance of midazolam in children following oromucosal administration is 30 ml/kg/min. Brentuximab vedotin toxicity includes The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML) follows infection by the JC virus (which is not related to Creutzfeldt-Jakob disease). Symptoms of this condition begin insidiously and usually worsen progressively. The symptoms vary depending on which region of the brain is infected. In about two out of three patients, mental function deteriorates rapidly, leading to dementia. Speaking and walking may become increasingly difficult. Vision may be impaired, and total blindness may occur. Rarely, headaches and seizures can occur, mainly in immunocompromised patients. The most serious sequela of this condition is death. Common adverse effects of Adcetris may include: neutropenia, anemia, peripheral neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and fever. In one trial, neutropenia occurred in 91 percent of patients treated with Adcetris plus chemotherapy, which was associated with a 19 percent rate of febrile neutropenia (neutropenia and fever). Preventive treatment with G-CSF, a growth factor for the bone marrow to produce white blood cells, is recommended with Adcetris plus chemotherapy for the first-line treatment of Stage III or IV cHL. Adcetris has a boxed warning that emphasizes the risk of John Cunningham virus infection leading to progressive multifocal leukoencephalopathy, or PML, a rare but serious brain infection that may be lethal. Serious risks of Adcetris include peripheral neuropathy; severe allergic (anaphylaxis) or infusion-site reactions; damage to the blood, lungs and liver (hematologic, pulmonary and hepato-toxicities); severe/opportunistic infections; metabolic abnormalities (tumor lysis syndrome); dermatologic reactions and gastrointestinal complications. Adcetris may cause harm to the fetus and newborn baby; women should be warned of the potential risk to the fetus and to use effective contraception, and to avoid breastfeeding while taking Adcetris. MMAE was found to be genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting drug. Fertility studies with Brentuximab vedotin or MMAE have not been conducted. Despite this, results of repeat-dose toxicity studies in rats suggest the potential for Brentuximab vedotin to have a negative effect on male reproductive function and fertility. In a 4-week repeated-dose toxicity study in rats with weekly dosing at 0. 5, 5 or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed. Effects in animals were seen mostly at 5 and 10 mg/kg doses of brentuximab vedotin. These dosages are approximately 3 and 6-fold the human recommended dose of 1. 8 mg/kg, respectively, based on individual body weight. Midazolam toxicity includes LD 50 =215 mg/kg, in rats. Overdose Signs of overdose include sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and deleterious effects on vital signs. Serious cardiorespiratory adverse reactions have occurred, sometimes ending in death or permanent neurologic effects, after the administration of midazolam. A note on cardiac and respiratory depression After administration of midazolam, continuous monitoring of respiratory and cardiac function is recommended until the patient is in stable condition. Serious and life-threatening cardiorespiratory adverse reactions, including hypoventilation, airway obstruction, apnea, and hypotension have been reported with the use of midazolam. Patients should be monitored in a setting with immediate access to resuscitative drugs if they are required. Resuscitation equipment and personnel trained in their use and skilled in airway management should be available when midazolam is administered. The usual recommended intramuscular pre-medicating doses of midazolam do not depress the ventilatory response to carbon dioxide stimulation to a clinically significant extent in adults. Intravenous induction doses of midazolam depress the ventilatory response to carbon dioxide stimulation for at least 15 minutes longer than the duration of ventilatory depression following administration of thiopental in adults. Impairment of ventilatory response to carbon dioxide is more severe in adult patients diagnosed with chronic obstructive pulmonary disease (COPD). A note on dependence When midazolam is used in long-term sedation in the ICU (intensive care unit) or other settings, physical dependence on midazolam may develop. The risk of dependence increases with dose and duration of treatment; this risk is also greater in patients with a medical history of substance abuse. Special caution should be exercised when administering midazolam in the following populations High-risk patients include adults over 60 years of age, chronically ill or debilitated patients, which may include patients with chronic respiratory insufficiency, patients with chronic renal failure, impaired hepatic function or with impaired cardiac function, pediatric patients (especially those with cardiovascular instability). These high-risk patients require lower dosages and should be monitored on a continuous basis for early signs of alterations of vital functions, so that appropriate management may be administered. Mutagenesis Midazolam was negative for genotoxicity during in vitro and in vivo assays. Impairment of Fertility When midazolam (0, 1, 4, or 16 mg/kg) was given orally to male and female rats before and during mating and continuing in females throughout gestation and lactation, no adverse effects on male or female fertility were observed. Midazolam plasma exposures (AUC) at the highest dose tested were approximately 6 times that in humans at the recomended human dose. Brand names of Brentuximab vedotin include Adcetris. Brand names of Midazolam include Buccolam, Busulfex, Nayzilam, Seizalam. No synonyms are available for Brentuximab vedotin. No synonyms are available for Midazolam. Brentuximab vedotin summary: It is Brentuximab vedotin is a CD30-directed antibody-drug conjugate used to treat various types of lymphoma. Midazolam summary: It is Midazolam is a short-acting benzodiazepine with rapid onset that is commonly used in seizures, anesthesia and anxiety disorders. Answer: Midazolam is metabolized by CYP3A4. 3 Pharmacokinetic interactions with CYP3A4 inhibitors are more pronounced for oral as compared to oromucosal or parenteral midazolam as CYP3A4 enzymes are also present in the upper gastro-intestinal tract. The magnitude of interaction with oral midazolam may be greater due to inhibition of CYP3A in both the intestine and liver, and the resultant decrease in first-pass metabolism of midazolam. Conversely, after oromucosal administration, only systemic clearance will be affected. After a single dose of oromucosal midazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. Furthermore, after a single dose of i. v. midazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. However, after prolonged dosing of midazolam, both the magnitude and duration of effect will be increased in the presence of CYP3A4 inhibition. Hence, careful monitoring of the clinical effects and vital signs is recommended during the use of midazolam with a CYP3A4 inhibitor even after a single dose.

Brentuximab vedotin

Drug A is Bezlotoxumab. Drug B is Isatuximab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Bezlotoxumab is combined with Isatuximab. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Bezlotoxumab is indicated for Bezlotoxumab is indicated to reduce the recurrence of Clostridioides difficile infection (CDI) in patients who are receiving antibacterial drug treatment for CDI and are at high risk for CDI recurrence. In the US, the drug is approved for use in patients one year of age and older. In Europe, it is approved in adults only. Isatuximab is indicated for Isatuximab is indicated in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma in adults who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. It is also indicated in combination carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy. Bezlotoxumab pharmacodynamics: Bezlotoxumab directly neutralizes the toxic effects of C. difficile by binding to the toxin with high affinity. In vitro, bezlotoxumab inhibited C. difficile toxin B-mediated expression of tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) in human peripheral blood monocyte cells and human colonic and explants. In clinical trials, the rate of recurrent C. difficile infection was lower in patients at risk for recurrent C. difficile infection receiving bezlotoxumab compared to placebo. The administration of bezlotoxumab plus actoxumab, another antibody directed against the C. difficile toxin resulted in dose-dependent protection against C. difficile toxin-induced damage and inflammation, as well as a reduced recurrence of C. difficile infection in mice. Isatuximab pharmacodynamics: Isatuximab results in the apoptosis of malignant plasma cells via inhibition of a surface protein key to their survival and proliferation. It has a relatively long residence time in the body, taking approximately 2 months to clear following the final dose, and may therefore be infused on a weekly or bimonthly schedule. Isatuximab is given in combination with pomalidomide due to a synergy that exists between the two - isatuximab can induce a depletion in host NK lymphocytes, yet the ADCC effect of anti-CD38 mAbs has been shown to be superior in patient samples with a high ratio of NK to myleoma cells. Pomalidomide, another antineoplastic agent, has the ability to induce and enhance NK lymphocyte activity and thus works synergistically to enhance isatuximab-mediated killing of myeloma cells. Isatuximab is formulated as an intravenous infusion and its administration may result in infusion-related reactions characterized most commonly by dyspnea, cough, chills, and nausea. All noted reactions started during the first infusion and 98% resolved on the same day. Reactions may be mitigated by pre-medication with acetaminophen, H2 antagonists, diphenyhdramine, and/or dexamethasone. Patients with grade 1 or 2 reactions may restart the infusion at a slower rate following resolution of symptoms, but patients experiencing a grade 3 or higher reaction (e. g. hypertension, bronchospasm) should discontinue therapy indefinitely. Isatuximab can generate false positive results for indirect antglobulin tests (indirect Coombs tests), immunofixation tests, and serum protein electrophoresis. The mechanism of action of Bezlotoxumab is that it C. difficile infections are caused by two exotoxins, toxin A and toxin B. Exotoxins are believed to bind to cell surface receptors expressed on colonocytes and are internalized via endocytosis. This process is followed by the acidification of the endosome, leading to a conformation change of the toxin, allowing for the transport of the endosome, autocleavage of the toxin via a cysteine protease domain, and the release of glucosyltransferase domain (GTD) from the endosome to the host cell cytoplasm. GTD glucosylates and inactivates small GTPases, such as Rac and Rho, critical for maintaining the actin cytoskeleton, cell adhesion, epithelial permeability, and other cellular function and homeostasis processes. Exotoxins eventually induce apoptosis and cell loss. Endotoxins also promote the release of proinflammatory mediators that recruit neutrophils and macrophages to the injury site, further aggravating the gut injury and damage. C. difficile infections are associated with a high risk of recurrence. Bezlotoxumab binds to C. difficile toxin B and neutralizes it. According to the findings of surface plasmon resonance analysis, bezlotoxumab binds to the toxin via two epitopes in the C-terminal CROP domain of the toxin, partially blocking the putative receptor binding pockets and preventing it from binding to host cell receptors. Bezlotoxumab does not bind to C. difficile toxin A. The mechanism of action of Isatuximab is that it Multiple myeloma is a blood cancer characterized by an overproduction of malignant plasma cells in the bone marrow. A unique characteristic of myeloma cells is their dense and uniform expression of CD38 surface glycoproteins - these proteins, also expressed in relatively minor quantities on other lymphoid and myeloid cells, have been identified as performing several critical cellular functions, and this, along with their relative abundance on myeloma cells, has made them an attractive target for multiple myeloma treatment. CD38 was first identified as an activation marker, but has subsequently demonstrated roles in adhesion to endothelial CD31 proteins, as an accessory component of the synapse complex, and as an ectoenzyme involved in the metabolism of extracellular NAD+ and cytoplasmic NADP. The products of CD38’s ectoenzymatic activity include the calcium-mobilizing compound adenosine diphosphate ribose (ADPR), which can be further metabolized by CD203a/PC-1 and CD73 to adenosine, an immunosuppressive molecule that may play a role in tumour cell evasion of the immune system. Isatuximab is an IgG1-derived monoclonal antibody targeted against CD38 proteins. Its activity against CD38 results in a number of downstream effects, including direct apoptosis of the affected cell and activation of immune mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC), all of which result in potent anti-tumour activity. Via allosteric antagonism, isatuximab also inhibits CD38 ectoenzymatic activity, preventing the immunosuppressive effects of its downstream products. Isatuximab may also exert its effects via downstream promotion of lysosome-dependent cell death, upregulation of reactive oxygen species, and restoration of antitumor immune effector cell functions. Bezlotoxumab absorption: After a single intravenous dose of 10 mg/kg bezlotoxumab, geometric mean AUC 0-∞ and Cmax were 53000 mcg x h/mL and 185 mcg/mL, respectively, in patients with CDI. Isatuximab absorption: When administered at the recommended dose and schedule, the steady-state Cmax and AUC were found to be 351 µg/mL and 72,600 μg∙h/mL, respectively. It takes approximately 8 weeks for isatuximab to reach steady-state. Over a dosage range of 1 mg/kg to 20 mg/kg given every 2 weeks AUC increases in a greater than dose-proportional manner, whereas over a dosage range of 5 mg/kg to 20 mg/kg every 4 weeks (followed by every 2 weeks) AUC was found to increase proportionately with dose. Steady-state AUC is lower in patients with increased body weight, but not to the extent that dose adjustments are required. Tmax ranges from approximately 2 to 5 hours, increasing with dose and with repeated dosing. The volume of distribution of Bezlotoxumab is Based on a population pharmacokinetic analysis, the geometric mean (%CV) volume of distribution was 7. 33 L (16%). The volume of distribution of Isatuximab is The predicted volume of distribution of isatuximab is 8. 13 L. Bezlotoxumab is No information is available. bound to plasma proteins. No protein binding information is available for Isatuximab. Bezlotoxumab metabolism: Bezlotoxumab undergoes protein catabolism. Isatuximab metabolism: Isatuximab metabolism is likely to involve catabolism to smaller proteins and peptides. Bezlotoxumab is eliminated via Bezlotoxumab is mainly eliminated by catabolism. Isatuximab is eliminated via No route of elimination available. The half-life of Bezlotoxumab is Based on a population pharmacokinetic analysis, the geometric mean (%CV) elimination half-life is approximately 19 days (28%). The half-life of Isatuximab is No half-life available. The clearance of Bezlotoxumab is Based on a population pharmacokinetic analysis, the geometric mean (%CV) clearance of bezlotoxumab was 0. 317 L/day (41%). The clearance of bezlotoxumab increased with increasing body weight: the resulting exposure differences are adequately addressed by the administration of a weight-based dose. The clearance of Isatuximab is Total clearance decreases with increasing dose and with multiple dosing. At steady-state, it takes approximately 2 months to eliminate ≥99% of isatuximab from plasma following the last dose. Bezlotoxumab toxicity includes The intravenous LD 50 was >125 mg/kg in mice. There is no clinical experience with the overdosage of bezlotoxumab. In clinical trials, healthy subjects received up to 20 mg/kg, which was generally well tolerated. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment should be instituted. Isatuximab toxicity includes There is no known antidote for isatuximab, nor does there appear to be any clinical experience with overdose. Symptoms of overdosage are likely to be consistent with isatuximab's adverse effect profile and may therefore include significant infusion-site reactions, gastrointestinal disturbances, and may increase the risk of infection. Treatment of overdose should involve careful monitoring of the patient and symptomatic and supportive measures as clinically indicated. Brand names of Bezlotoxumab include Zinplava. Brand names of Isatuximab include Sarclisa. No synonyms are available for Bezlotoxumab. No synonyms are available for Isatuximab. Bezlotoxumab summary: It is Bezlotoxumab is a monoclonal antibody used to reduce the recurrence of Clostridium difficile infections. Isatuximab summary: It is Isatuximab is a chimeric monoclonal antibody targeted against surface CD38 glycoproteins for the treatment of multiple myeloma in patients who have failed previous therapies. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Bezlotoxumab

Drug A is Peginterferon alfa-2b. Drug B is Fluticasone propionate. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Peginterferon alfa-2b is combined with Fluticasone propionate. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Peginterferon alfa-2b is indicated for Peginterferon alfa-2b is indicated for the treatment of HCV in combination with Ribavirin and a NS3/4A protease inhibitor for genotype 1 or without a NS3/4A protease inhibitor for genotypes 2-6. May be used as a monotherapy in patients with contraindications to or significant intolerance to other anti-viral therapies. It is also indicated for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy. Fluticasone propionate is indicated for Fluticasone propionate is indicated as an inhaler for the treatment and management of asthma by prophylaxis as well as inflammatory and pruritic dermatoses. Fluticasone propionate nasal spray is indicated for managing allergic and nonallergic rhinitis. Peginterferon alfa-2b pharmacodynamics: Peginterferon alfa-2b inhibits viral replication in infected cells, suppresses cell proliferation, induces apoptosis, and exerts an anti-angiogenic effect. Exerts immunomodulatory effects such as enhancement of the phagocytic activity of macrophages, activation of NK cells, stimulation of cytotoxic T-lymphocytes, and the upregulation of the Th1 T-helper cell subset. Also increases concentrations of effector proteins such as serum neopterin and 2'5' oligoadenylate synthetase, raises body temperature, and causes reversible decreases in leukocyte and platelet counts. Fluticasone propionate pharmacodynamics: Systemically, fluticasone propionate activates glucocorticoid receptors, and inhibits lung eosinophilia in rats. Fluticasone propionate as a topical formulation is also associated with vasoconstriction in the skin. The mechanism of action of Peginterferon alfa-2b is that it Peginterferon alfa-2b is derived from recombinant human interferon's alfa-2b moeity. It binds to and activates human type 1 interferon receptors causing them to dimerize. This activates the JAK/STAT pathway. Activation of the JAK/STAT pathway increases expression of multiple genes in multiple tissues involved in the innate antiviral response. Peginterferon alfa-2b may also acitvate the nuclear factor κB pathway. The mechanism of action of Fluticasone propionate is that it Fluticasone propionate works through an unknown mechanism to affect the action of various cell types and mediators of inflammation. Fluticasone propionate activates glucocorticoid receptors and inhibits lung eosinophilia in rats. Peginterferon alfa-2b absorption: Peginterferon alfa-2b reaches peak plasma concentration 15-44 hours after subcutaneous administration. The mean absorption half-life is 4. 6 hours. After multiple doses the bioavailability of Peginterferon alfa-2b increases with trough concentrations at week 48 3-fold higher than those at week 4. Fluticasone propionate absorption: Intranasal bioavailability of fluticasone propionate is <2%, and oral bioavailability is <1%. Intranasal exposure results in the majority of the dose being swallowed. Topical absorption of fluticasone propionate is very low but can change depending on a number of factors including integrity of the skin and the presence of inflammation or disease. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 9. 0%. No volume of distribution information is available for Peginterferon alfa-2b. The volume of distribution of Fluticasone propionate is The volume of distribution of intravenous fluticasone propionate is 4. 2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration. No protein binding information is available for Peginterferon alfa-2b. Fluticasone propionate is Fluticasone propionate is 99% protein bound in serum. Topical fluticasone propionate is only 91% protein bound in serum however. bound to plasma proteins. No metabolism information is available for Peginterferon alfa-2b. Fluticasone propionate metabolism: Fluticasone propionate is cleared from hepatic metabolism by cytochrome P450 3A4. Fluticasone propionate is hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite. Peginterferon alfa-2b is eliminated via Renal elimination accounts for 30% of Peginterferon alfa-2b elimination. Fluticasone propionate is eliminated via Fluticasone propionate is mainly eliminated in the feces with <5% eliminated in the urine. The half-life of Peginterferon alfa-2b is The mean half-life of elimination of Peginterferon alfa-2b is 40 hours in a range of 22-60 hours. The half-life of Fluticasone propionate is 7. 8 hours for intravenous fluticasone propionate. A study of 24 healthy Caucasian males shows a half life of 14. 0 hours following intravenous administration and 10. 8 hours following inhalation. The clearance of Peginterferon alfa-2b is The estimated apparent clearance of Peginterferon alfa-2b is 22 milliters per hour per kilogram. The clearance of Fluticasone propionate is 1093mL/min for fluticasone propionate. A study of 24 healthy Caucasian males showed a clearance of 63. 9L/h following intravenous administration. Peginterferon alfa-2b toxicity includes Peginterferon alfa-2b may manifest neuropsychiatric complications include suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose. Hypertension, supraventricular arrhythmias, chest pain, and myocardial infarction have been observed in patients using Peginterferon alfa-2b. Peginterferon alfa-2b may produce myelosuppression as well as the development or aggravation of autoimmune disorders including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus. Peginterferon alfa-2b causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with Peginterferon alfa-2b. Peginterferon alfa-2b may decrease or produce loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema and serous retinal detachment. Peginterferon mayy be related to increased ischemic and hemorrhagic cerebrovascular events. Patients with cirrhosis on Peginterferon alfa-2b are at risk of hepatic decompensation. Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis may be induced or aggravated by Peginterferon alfa-2b. Serious and severe infections (bacterial, viral, or fungal) have been reported during treatment with Peginterferon alfa-2b. Ulcerative and hemorrhagic/ischemic colitis have been observed within 12 weeks of starting Peginterferon alfa-2b treatment. Pancreatitis and peripheral nephropathy have also been reported. Peginterferon alfa-2b is associated with growth inhibition in pediatric patients. Use of Peginterferon alfa-2b while pregant may result in delopmental abnormalities or death of the fetus. Fluticasone propionate toxicity includes Fluticasone propionate's use in specific populations has not been well studied. Fluticasone propionate is not carcinogenic, mutagenic, or clastogenic, nor did it affect fertility in animal studies. Subcutaneous fluticasone propionate has been shown to produce teratogenic effects in rats though oral administration does not. Generally, there are no reported adverse effects with fluticasone in pregnancy. Fluticasone propionate in human milk may cause growth suppression, effects on endogenous corticosteroid production, or other effects. Pediatric patients treated with fluticasone propionate ointment experienced adrenal suppression. Geriatric patients treated with fluticasone propionate did not show any difference in safety or efficacy compared to other patient groups, though older patients may be more sensitive to adverse effects. There is no difference in the clearance of fluticasone propionate across genders or race. Patients with hepatic impairment should be closely monitored due to the elimination mechanism. Brand names of Peginterferon alfa-2b include Pegintron, Sylatron. Brand names of Fluticasone propionate include Advair, Airduo, Airduo Respiclick, Aller-flo, Armonair, Beser, Cutivate, Dymista, Flonase, Flovent, Fluticare, Ticanase, Wixela, Xhance. No synonyms are available for Peginterferon alfa-2b. No synonyms are available for Fluticasone propionate. Peginterferon alfa-2b summary: It is Peginterferon alfa-2b is a purified form of human interferon used to stimulate the innate antiviral response in the treatment of hepatitis B and C, genital warts, and some cancers. Fluticasone propionate summary: It is Fluticasone propionate is a glucocorticoid used to treat asthma, inflammatory pruritic dermatoses, and nonallergic rhinitis. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Peginterferon alfa-2b

Drug A is Bevacizumab. Drug B is Eftrenonacog alfa. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Bevacizumab is combined with Eftrenonacog alfa. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Bevacizumab is indicated for As a vascular endothelial growth factor (VEGF) inhibitor, bevacizumab is used in several chemotherapy regimens to treat metastatic colorectal cancer; metastatic, unresectable, locally advanced or recurrent non-squamous non-small cell lung cancer; metastatic renal cell carcinoma; metastatic, persistent, or recurrent cervical cancer; primary peritoneal cancer; epithelial ovarian cancer; fallopian tube cancer; breast cancer; and recurrent glioblastoma. Interestingly, bevacizumab is currently under investigation for the treatment of COVID-19 complications including acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Eftrenonacog alfa is indicated for Indicated for the treatment and prophylaxis of bleeding in patients of all age with haemophilia B (congenital factor IX deficiency). Bevacizumab pharmacodynamics: Bevacizumab binds circulating vascular endothelial-derived growth factor (VEGF) and blocks it from binding to its associated receptors, effectively blunting downstream signaling. The effects of bevacizumab have been shown to re-establish normal vasculature at the tumor site resulting in increased nutrient and oxygen supply, while also improving the delivery of chemotherapeutic drugs to the target area. On the other hand, VEGF signaling is a vital component of several processes including angiogenesis, lymphangiogenesis, blood pressure regulation, wound healing, coagulation, and renal filtration. Although blocking VEGF may inhibit metastatic disease progression, it may also result in unintended effects due to the role of VEGF in several other physiologic processes. Eftrenonacog alfa pharmacodynamics: In two multinational, phase III studies in previously treated children, adolescents and adults with severe haemophilia B, eftrenonacog alfa prophylaxis resulted in low median annualized bleeding rates (ABRs), and was associated with reductions in median weekly factor consumption and dosing frequency compared with pre-study FIX regimens. The extension of those studies demonstrated effectiveness in the treatment of bleeding episodes and when used in the perioperative setting in all age groups. In animal models, a single intravenous dose of eftrenonacog alfa displayed half values approximately three- to four-fold longer than those seen with recombinant FIX. The mechanism of action of Bevacizumab is that it Transcription of the VEGF protein is induced by 'hypoxia inducible factor' (HIF) in a hypoxic environment. When circulating VEGF binds to VEGF receptors (VEGFR-1 and VEGFR-2) located on endothelial cells, various downstream effects are initiated. It should be noted that VEGF also binds to the neuropilin co-receptors (NRP-1 and NRP-1), leading to enhanced signaling. Cancer cells promote tumor angiogenesis by releasing VEGF, resulting in the creation of an immature and disorganized vascular network. The hypoxic microenvironment promoted by cancer cells favors the survival of more aggressive tumor cells, and gives rise to a challenging environment for immune cells to respond appropriately. As a result, VEGF has become a well-known target for anti-cancer drugs like bevacizumab. Bevacizumab is a mAb that exerts its effects by binding and inactivating serum VEGF. When bound to the mAb, VEGF is unable to interact with its cell surface receptors, and proangiogenic signalling is inhibited. This prevents formation of new blood vessels, decreases tumor vasculature, and reduces tumor blood supply. There is also evidence to suggest that VEGF is upregulated in COVID-19 patients, hence, bevacizumab is being investigated for the treatment of associated complications. Higher levels of VEGF may contribute to pulmonary edema, leading to acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Researchers are hopeful that by inhibiting VEGF, bevacizumab may effectively treat ARDS and ALI - both common features of severe COVID-19 cases. The mechanism of action of Eftrenonacog alfa is that it The coagulation protein factor IX (FIX) is a vitamin K-dependent coagulation factor and one of the critical serine proteases involved in the coagulation cascade. Upon activation by factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway, factor IX, in combination with factor VIII, activates factor X. Activated factor X mediates the conversion of prothrombin to thrombin which sequentially leads to thrombin converting fibrinogen into fibrin. A blood clot is then formed. With a mutation in the gene encoding the coagulation protein factor IX (FIX), patients with hemophilia B have factor IX deficiency and are at high risk for recurrent bleeding episodes. Eftrenonacog alfa is composed of a single molecule of recombinant FIX (rFIX) covalently fused to the dimeric Fc domain of immunoglobulin (Ig) G1 (rFIXFc). It serves as a replacement therapy to increase the plasma levels of factor IX thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies. The Fc region of human immunoglobulin G1 binds with the neonatal Fc receptor which is expressed throughout life as part of a naturally occurring pathway that protects immunoglobulins from lysosomal degradation by cycling these proteins back into circulation, resulting in their long plasma half-life. The binding of eftrenonacog alfa to the neonatal Fc receptor delays degradation and recycles the fusion protein back into circulation for increased plasma half life and prolonged therapeutic action. Bevacizumab absorption: Monoclonal antibodies (mAbs) are large in size, do not readily cross cell membranes, and are unable to withstand proteolysis in the gastrointestinal tract. Given these characteristics, mAbs are poorly absorbed via the oral route and are instead administered intravenously, intramuscularly or subcutaneously. In a single dose (1mg/kg) pharmacokinetic study assessing the bioequivalence of bevacizumab and TAB008 (a biosimilar product), the pharmacokinetic parameters of Avastin (bevacizumab) were as follows:. Geometric mean Cmax = 17. 38 ug/mL Geometric mean AUCinf = 5,358 ugxh/mL Geometric mean Tmax = 2. 50 hrs Eftrenonacog alfa absorption: Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean peak plasma concentration (Cmax) was 46. 10 IU/dL. The mean area under the FIX activity time curve (AUC) was 31. 58 Uxh/dL per IU/kg. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean AUC ranged from 22. 71 to 29. 50 Uxh/dL per IU/kg. The volume of distribution of Bevacizumab is The volume of distribution of bevacizumab is approximately 3. 29 L and 2. 39 L for the average male and female, respectively. The volume of distribution of Eftrenonacog alfa is Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean volume of distribution at steady-state (Vss) was 303. 4 mL/kg. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean Vss ranged from 289 to 365. 1 mL/kg. Bevacizumab is >97% of serum VEGF is bound to bevacizumab. bound to plasma proteins. No protein binding information is available for Eftrenonacog alfa. Bevacizumab metabolism: There are several pathways through which monoclonal antibodies (mAbs) may be cleared. Non-specific clearance of mAbs refers to target independent pinocytosis, and proteolysis of the protein into small amino acids and peptides in the reticuloendothelial system (RES) and the liver. Target-mediated clearance is a result of specific interactions between the mAb and its target antigen. Once bound, the antibody-antigen complex may be cleared via lysosomal degradation. Additionally, the production of anti-drug antibodies (ADA), which are a result of an immunogenic response to mAb-based treatment, can form complexes with mAb’s and may impact the rate of mAb clearance. Eftrenonacog alfa metabolism: The Fc domain of eftrenonacog alfa is expected to undergo lysosomal degradation while the remaining recombinant FIX (rFIX) portion is expected to be metabolized by the same pathway as endogenous factor IX. Bevacizumab is eliminated via Due to their size, monoclonal antibodies are not renally eliminated under normal physiological conditions. Catabolism or excretion are the primary processes of elimination. Eftrenonacog alfa is eliminated via Eftrenonacog alfa is expected to undergo renal clearance. The half-life of Bevacizumab is The half-life of bevacizumab is estimated to be 20 days (range of 11-50 days). The half-life of Eftrenonacog alfa is Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean terminal half life (t1/2) was 77. 6 hours. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean t1/2 ranged from 66. 49 to 82. 22 hours. The clearance of Bevacizumab is The clearance (CL) of bevacizumab is approximately 0. 207 L/day. The CL of bevacizumab can increase or decrease by 30% in patients who weigh >114 kg or <49 kg respectively. Males tend to clear bevacizumab at a faster rate than females (26% faster on average). Other factors including alkaline phosphatase (ALP), serum aspartate aminotransferase (AST), serum albumin, and tumor burden may cause the CL to fluctuate. The clearance of Eftrenonacog alfa is Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean clearance (CL) was 3. 17 mL/h/kg. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, mean CL ranged from 3. 390 to 4. 365 mL/h/kg. Bevacizumab toxicity includes Bevacizumab toxicities are distinct from the effects of cytotoxic agents used in chemotherapy, and are normally linked to impaired VEGF function. Common toxicities associated with bevacizumab include hypertension, gastrointestinal perforation, arterial thromboembolism, reversible posterior leukoencephalopathy syndrome (RPLS), venous thromboembolism, proteinuria, bleeding/hemorrhage, and wound-healing complications. Eftrenonacog alfa toxicity includes Based on findings from a rabbit thrombogenicity test and rat or monkey repeated-dose toxicity studies, eftrenonacog alfa displays no special hazards for humans. Studies to investigate the genotoxicity, carcinogenicity, toxicity to reproduction or embryo-foetal development have not been conducted. Eftrenonacog alfa has shown to cross the placenta in small amounts according to a mouse placental transfer study. Brand names of Bevacizumab include Avastin, Mvasi. Brand names of Eftrenonacog alfa include Alprolix. No synonyms are available for Bevacizumab. No synonyms are available for Eftrenonacog alfa. Bevacizumab summary: It is Bevacizumab is a monoclonal anti-vascular endothelial growth factor antibody used in combination with antineoplastic agents for the treatment of many types of cancer. Eftrenonacog alfa summary: It is Eftrenonacog alfa is a recombinant Factor IX used to treat and prevent bleeding in hemophilia B. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Bevacizumab

Drug A is Polatuzumab vedotin. Drug B is Bevacizumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Bevacizumab is combined with Polatuzumab vedotin. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Polatuzumab vedotin is indicated for Polatuzumab vedotin is used in combination with bendamustine and rituximab to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, after at least two prior therapies. In Canada, this indication is approved for patients who are not eligible for autologous stem cell transplant and have received at least one prior therapy. Polatuzumab vedotin is also used in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) to treat adult patients with previously untreated large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), high-grade B-cell lymphoma, Epstein-Barr virus-positive (EBV+) DLBCL NOS, and T-cell/histiocyte rich LBCL. Bevacizumab is indicated for As a vascular endothelial growth factor (VEGF) inhibitor, bevacizumab is used in several chemotherapy regimens to treat metastatic colorectal cancer; metastatic, unresectable, locally advanced or recurrent non-squamous non-small cell lung cancer; metastatic renal cell carcinoma; metastatic, persistent, or recurrent cervical cancer; primary peritoneal cancer; epithelial ovarian cancer; fallopian tube cancer; breast cancer; and recurrent glioblastoma. Interestingly, bevacizumab is currently under investigation for the treatment of COVID-19 complications including acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Polatuzumab vedotin pharmacodynamics: Polatuzumab vedotin is an anti-cancer agent that works to cause apoptosis in malignant B cells. In vitro, it exerted cytotoxic effects on most diffuse large B-cell lymphoma (DLBCL) cell lines: this effect was consistent across cell lines, regardless of the cell-of-origin subtypes and whether they harboured mutations in the CD79B gene or not. In mouse xenograft models, polatuzumab vedotin caused apoptosis and reduced proliferation of mature CD79b+ B-cell NHL cell lines. Polatuzumab vedotin can cause immunosuppression, including neutropenia and thrombocytopenia. Bevacizumab pharmacodynamics: Bevacizumab binds circulating vascular endothelial-derived growth factor (VEGF) and blocks it from binding to its associated receptors, effectively blunting downstream signaling. The effects of bevacizumab have been shown to re-establish normal vasculature at the tumor site resulting in increased nutrient and oxygen supply, while also improving the delivery of chemotherapeutic drugs to the target area. On the other hand, VEGF signaling is a vital component of several processes including angiogenesis, lymphangiogenesis, blood pressure regulation, wound healing, coagulation, and renal filtration. Although blocking VEGF may inhibit metastatic disease progression, it may also result in unintended effects due to the role of VEGF in several other physiologic processes. The mechanism of action of Polatuzumab vedotin is that it Polatuzumab vedotin is an antibody-drug conjugate consisting of a CD79b-directed antibody, a microtubule-disrupting agent called monomethyl auristatin E (MMAE), and a cleavable linker that holds the components together. CD79 is a heterodimer composed of CD79a and CD79b. Responsible for signal transduction, CD79 forms a complex with the B cell receptor (BCR) and is almost exclusively expressed on B cells, including malignant B cells. Most importantly, CD79b gained increasing attention as a promising therapeutic target as it plays an essential role in BCR expression, transport, and functions such as B cell proliferation and differentiation. Once the antibody component binds to CD79b, polatuzumab vedotin is internalized, and lysosomal proteases cleave the linker to release MMAE in the cell. MMAE is a microtubule-disrupting anti-mitotic agent that exerts cytotoxic effects against malignant B cells. It binds to microtubules, inhibits mitosis by interfering with tubulin and tubulin polymerization, and induces apoptosis in dividing B cells. The mechanism of action of Bevacizumab is that it Transcription of the VEGF protein is induced by 'hypoxia inducible factor' (HIF) in a hypoxic environment. When circulating VEGF binds to VEGF receptors (VEGFR-1 and VEGFR-2) located on endothelial cells, various downstream effects are initiated. It should be noted that VEGF also binds to the neuropilin co-receptors (NRP-1 and NRP-1), leading to enhanced signaling. Cancer cells promote tumor angiogenesis by releasing VEGF, resulting in the creation of an immature and disorganized vascular network. The hypoxic microenvironment promoted by cancer cells favors the survival of more aggressive tumor cells, and gives rise to a challenging environment for immune cells to respond appropriately. As a result, VEGF has become a well-known target for anti-cancer drugs like bevacizumab. Bevacizumab is a mAb that exerts its effects by binding and inactivating serum VEGF. When bound to the mAb, VEGF is unable to interact with its cell surface receptors, and proangiogenic signalling is inhibited. This prevents formation of new blood vessels, decreases tumor vasculature, and reduces tumor blood supply. There is also evidence to suggest that VEGF is upregulated in COVID-19 patients, hence, bevacizumab is being investigated for the treatment of associated complications. Higher levels of VEGF may contribute to pulmonary edema, leading to acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Researchers are hopeful that by inhibiting VEGF, bevacizumab may effectively treat ARDS and ALI - both common features of severe COVID-19 cases. Polatuzumab vedotin absorption: After the first polatuzumab vedotin dose of 1. 8 mg/kg, the mean (± SD) Cmax of antibody-conjugated MMAE and unconjugated MMAE were 803 (± 233) ng/mL and 6. 82 (± 4. 73) ng/mL, respectively. The mean AUC inf of antibody-conjugated MMAE and unconjugated MMAE were 1860 (± 966) day x ng/mL and 52. 3 (± 18. 0) day x ng/mL, respectively. Bevacizumab absorption: Monoclonal antibodies (mAbs) are large in size, do not readily cross cell membranes, and are unable to withstand proteolysis in the gastrointestinal tract. Given these characteristics, mAbs are poorly absorbed via the oral route and are instead administered intravenously, intramuscularly or subcutaneously. In a single dose (1mg/kg) pharmacokinetic study assessing the bioequivalence of bevacizumab and TAB008 (a biosimilar product), the pharmacokinetic parameters of Avastin (bevacizumab) were as follows:. Geometric mean Cmax = 17. 38 ug/mL Geometric mean AUCinf = 5,358 ugxh/mL Geometric mean Tmax = 2. 50 hrs The volume of distribution of Polatuzumab vedotin is The estimated central volume of distribution of polatuzumab vedotin based on population PK analysis is 3. 15 L. The volume of distribution of Bevacizumab is The volume of distribution of bevacizumab is approximately 3. 29 L and 2. 39 L for the average male and female, respectively. Polatuzumab vedotin is MMAE is 71% to 77% bound to plasma proteins. Its blood-to-plasma ratio is 0. 79 to 0. 98, in vitro. bound to plasma proteins. Bevacizumab is >97% of serum VEGF is bound to bevacizumab. bound to plasma proteins. Polatuzumab vedotin metabolism: Polatuzumab vedotin is expected to undergo catabolism into small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. MMAE is metabolized by CYP3A4/5. Bevacizumab metabolism: There are several pathways through which monoclonal antibodies (mAbs) may be cleared. Non-specific clearance of mAbs refers to target independent pinocytosis, and proteolysis of the protein into small amino acids and peptides in the reticuloendothelial system (RES) and the liver. Target-mediated clearance is a result of specific interactions between the mAb and its target antigen. Once bound, the antibody-antigen complex may be cleared via lysosomal degradation. Additionally, the production of anti-drug antibodies (ADA), which are a result of an immunogenic response to mAb-based treatment, can form complexes with mAb’s and may impact the rate of mAb clearance. Polatuzumab vedotin is eliminated via Polatuzumab vedotin is predominantly excreted in feces, as well as in urine to some extent. Bevacizumab is eliminated via Due to their size, monoclonal antibodies are not renally eliminated under normal physiological conditions. Catabolism or excretion are the primary processes of elimination. The half-life of Polatuzumab vedotin is The terminal half-life of polatuzumab vedotin is approximately 12 days (95% CI: 8. 1 to 19. 5 days) at Cycle 6. The terminal half-life of unconjugated MMAE is approximately four days after the first dose of polatuzumab vedotin. The half-life of Bevacizumab is The half-life of bevacizumab is estimated to be 20 days (range of 11-50 days). The clearance of Polatuzumab vedotin is The predicted clearance of polatuzumab vedotin is 0. 9 L/day. The clearance of Bevacizumab is The clearance (CL) of bevacizumab is approximately 0. 207 L/day. The CL of bevacizumab can increase or decrease by 30% in patients who weigh >114 kg or <49 kg respectively. Males tend to clear bevacizumab at a faster rate than females (26% faster on average). Other factors including alkaline phosphatase (ALP), serum aspartate aminotransferase (AST), serum albumin, and tumor burden may cause the CL to fluctuate. Polatuzumab vedotin toxicity includes Data regarding overdoses and LD 50 are not readily available. Bevacizumab toxicity includes Bevacizumab toxicities are distinct from the effects of cytotoxic agents used in chemotherapy, and are normally linked to impaired VEGF function. Common toxicities associated with bevacizumab include hypertension, gastrointestinal perforation, arterial thromboembolism, reversible posterior leukoencephalopathy syndrome (RPLS), venous thromboembolism, proteinuria, bleeding/hemorrhage, and wound-healing complications. Brand names of Polatuzumab vedotin include Polivy. Brand names of Bevacizumab include Avastin, Mvasi. No synonyms are available for Polatuzumab vedotin. No synonyms are available for Bevacizumab. Polatuzumab vedotin summary: It is Polatuzumab vedotin is a CD79b antibody conjugate indicated to treat different types of large B-cell lymphoma. Bevacizumab summary: It is Bevacizumab is a monoclonal anti-vascular endothelial growth factor antibody used in combination with antineoplastic agents for the treatment of many types of cancer. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Polatuzumab vedotin

Drug A is Anakinra. Drug B is Apixaban. The severity of the interaction is moderate. The metabolism of Apixaban can be increased when combined with Anakinra. The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. Anakinra is indicated for Anakinra is an interleukin-1 receptor antagonist indicated for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis (RA), in patients 18 years of age or older who have failed one or more disease-modifying antirheumatic drugs (DMARDs). Anakinra can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents. Anakinra is also indicated for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID) and the treatment of Deficiency of Interleukin-1 Receptor Antagonist (DIRA). Anakinra is also used off-label for the treatment of several inflammatory diseases. The FDA has issued an emergency use authorization (EUA) for the emergency use of anakinra for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults with positive results of direct SARS-CoV-2 viral testing with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR). Since anakinra is approved for this condition under EUA, the drug should only be used when there are no alternative treatment available. Apixaban is indicated for Apixaban is indicated for reducing the risk of stroke and systemic embolism in patients who have nonvalvular atrial fibrillation, prophylaxis of deep vein thrombosis(DVT) leading to pulmonary embolism(PE) in patients after a hip or knee replacement surgery, and treatment of DVT and PE to reduce the risk of recurrence. Anakinra pharmacodynamics: Anakinra is a recombinant human interleukin-1 receptor antagonist (IL-1Ra) that blocks the biologic activity of interleukin-1 (IL-1) by competitively inhibiting its ability to bind to the IL-1 type I receptor (IL-1RI). IL-1 production is higher in inflammatory diseases such as rheumatoid arthritis, where the amount of naturally occurring IL-1Ra cannot compete with the high level of IL-1 present. Anakinra has been associated with a higher probability of developing a severe infection, and the use of TNF blocking agents can increase this incidence. Hypersensitivity reactions have been reported in patients using anakinra. The prevalence of allergic reactions may be higher in patients with deficiency of interleukin-1 receptor antagonist (DIRA), since they lack the naturally occurring IL-1Ra. Anakinra can also decrease neutrophil counts in patients. Therefore, neutrophil counts should be assessed before initiating anakinra. Apixaban pharmacodynamics: Apixaban selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III. Apixaban also inhibits prothrominase. These effects prevent the formation of a thrombus. The mechanism of action of Anakinra is that it Interleukin-1 (IL-1) plays an important role in inflammation and immunological responses. Inflammatory stimuli trigger its production, and it binds to the IL-1 receptor to activate a wide variety of mechanisms. The activity of the IL-1 receptor is also regulated by a naturally occurring IL-1 receptor antagonist (IL-1Ra) that competes for the binding sites of the IL-1 receptor. In rheumatoid arthritis (RA) patients, IL-1 levels are elevated, inducing cartilage degradation and the stimulation of bone resorption, and the amount of IL-1Ra in the synovium and synovial fluid of RA patients cannot compete with the high level of IL-1 present. Anakinra is a recombinant, non-glycosylated form of IL-1Ra that competes with and inhibits IL-1 by binding to the IL-1 receptor; therefore, the administration of this drug reduces the inflammatory response in RA patients. Anakinra can also be used in the treatment of neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of interleukin-1 receptor antagonist (DIRA). Patients with NOMID have spontaneous mutations in CIAS1/NLRP3, a gene that encodes cryopyrin, an inflammasome component. When activated, the inflammasome enhances and promotes the production of IL-1β, an isoform of IL-1. DIRA is an autoinflammatory disease caused by mutations in the IL1RN gene. These mutations reduce the amount of IL-1Ra that is secreted, leading to the unopposed action of IL-1. Anakinra controls NOMID and DIRA symptoms by inhibiting IL-1 activity. The mechanism of action of Apixaban is that it Apixaban selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III. Apixaban also inhibits prothrominase. These effects prevent the formation of a thrombus. Anakinra absorption: The bioavailability of anakinra is 95% in healthy subjects administered a 70 mg subcutaneous bolus injection. In patients with rheumatoid arthritis (RA) administered a subcutaneous dose of anakinra, the maximum plasma concentration was detected 3 to 7 hours later. No unexpected accumulation was observed in RA patients receiving this drug for up to 24 weeks. In a phase 1, single-center, randomized, sequential single-dose escalation PK study done in patients with stable RA, AUC increased in a relatively dose-proportional manner. While the t max and Cmax fluctuated across the different doses provided to these patients (range from 0. 5 to 6 mg/kg), clearance appeared to be consistent. In patients with neonatal-onset multisystem inflammatory disease (NOMID) treated with a subcutaneous dose of 3 mg/kg of anakinra for an average of 3. 5 years (n=16), Cmax was 3628 ng/mL and C 24h was 203 ng/mL. Apixaban absorption: Apixaban is approximately 50% bioavailable though other studies report 43-46% oral bioavailability. The volume of distribution of Anakinra is In adult subjects with rheumatoid arthritis (RA) treated with anakinra (n=35), the volume of distribution averaged 18. 5 L. The volume of distribution of Apixaban is Approximately 21L. No protein binding information is available for Anakinra. Apixaban is 92-94%. bound to plasma proteins. Anakinra metabolism: As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body. Apixaban metabolism: 50% of the orally administered dose is excreted as the unchanged parent compound, however 25% of the dose is excreted as O-demethyl apixaban sulfate. All apixaban metabolites account for approximately 32% of the excreted dose though the structure of all metabolites are not well defined. Apixaban is mainly metabolized by cytochrome p450(CYP)3A4 and to a lesser extent by CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2. Anakinra is eliminated via Anakinra is mostly excreted by the kidney; therefore, the risk of toxic reactions may increase in patients with impaired renal function. Apixaban is eliminated via 56% of an orally administered dose is recovered in the feces and 24. 5-28. 8% of the dose is recovered in the urine. 83-88% of the dose recovered in the urine was the unchanged parent compound. The half-life of Anakinra is In patients with rheumatoid arthritis (RA), the terminal half-life of anakinra ranged from 4 to 6 hours. In patients with neonatal-onset multisystem inflammatory disease (NOMID), the median half-life of anakinra was 5. 7 h (range=3. 1-28. 2, n=12). The half-life of Apixaban is 12. 7±8. 55h. The clearance of Anakinra is In patients with rheumatoid arthritis (RA), the clearance of anakinra was relatively consistent for different dose levels. Clearance is variable and increases with increasing creatinine clearance and body weight. However, gender and age were not significant factors. In patients with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal impairment, the mean plasma clearance of anakinra was 16% and 50% lower, respectively. In patients with severe renal insufficiency and end-stage renal disease (creatinine clearance < 30 mL/min), the mean plasma clearance of anakinra was 70% and 75% lower, respectively. The clearance of Apixaban is 3. 3L/h though other studies report 4876mL/h. Anakinra toxicity includes In clinical trials done in patients with rheumatoid arthritis (RA) and neonatal-onset multisystem inflammatory disease (NOMID) treated with anakinra, no cases of overdose were reported. Sepsis trials were performed using mean calculated doses up to 35 times the ones given to patients with RA over 72 hours. Anakinra did not produce any serious toxicities at this dose range. In preclinical studies done in rats, where up to 100 mg/kg/day were administered either intravenously or subcutaneously over 14 days, and given at doses of 2, 20 or 200 mg/kg/day subcutaneously for 6 months, anakinra was well tolerated. Toxicity ranged from mild to moderate, and dose-related inflammation, hemorrhage and fibrosis at the injection site were detected in both rats and monkeys. The no observable adverse effect level (NOAEL) in rats receiving a daily subcutaneous dose of anakinra for 6 months was 2 mg/kg/day. In rats receiving a daily intravenous injection of anakinra for 14 or 28 days, the NOAEL was 30 mg/kg/day. The NOAEL in Rhesus monkeys was 150 mg/kg/day when anakinra was administered via intravenous infusion for 7 days, 10-30 mg/kg/day when administered via intravenous bolus injection for 14 days and 5 mg/kg/day when administered subcutaneously for 14 days. Anakinra had no effects on fertility and reproductive capacity in both male and female rats given the maximum recommended human dose. Apixaban toxicity includes Animal studies have shown an increased risk of maternal bleeding during pregnancy but no increase in fetal malformations or fetal or maternal deaths. It is unknown if this animal data also translates to humans so apixaban should only be used in pregnancy if the benefits outweigh the risks. It is not know whether apixaban is safe and effective in labor and during birth, though animal studies have shown an increased rate of maternal bleeding. Animal studies in rats show apixaban excreted in milk, though it is not know if this also applies to humans. Nursing mothers should either stop breastfeeding or stop taking apixaban depending on the risk and benefit of each option. Studies to determine safety and effectiveness in pediatric patients have yet to be performed. Studies that involved geriatric patients (at least 75 years old) saw no difference in safety or effectiveness compared to younger patients, though geriatric patients at an especially advanced age may be more susceptible to adverse effects. Dosage adjustments for patients with end stage renal disease(ESRD) are based on estimates of pharmacokinetic principles and not clinical study. Patients with ESRD may experience pharmacodynamics similar to those seen in well controlled studies but it may not lead to the same clinical effects. Dosage adjustments are not necessary in mild hepatic impairment. In moderate hepatic impairment patients may already experience abnormalities in coagulation and so no dose recommendations are possible. Apixaban is not recommended for patients with severe hepatic impairment. Brand names of Anakinra include Kineret. Brand names of Apixaban include Eliquis. No synonyms are available for Anakinra. No synonyms are available for Apixaban. Anakinra summary: It is Anakinra is a recombinant form of human interleukin-1 receptor antagonist used in the treatment of rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and deficiency of interleukin-1 receptor antagonist (DIRA). Apixaban summary: It is Apixaban is an anticoagulant used for the prophylaxis of stroke and systemic embolism in nonvalvular atrial fibrillation, and deep vein thrombosis(DVT) leading to pulmonary embolism(PE), including in patients after a hip or knee replacement surgery. Answer: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates.

Anakinra

Drug A is Acetylsalicylic acid. Drug B is Oxacillin. The severity of the interaction is minor. Acetylsalicylic acid may decrease the excretion rate of Oxacillin which could result in a higher serum level. The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. Oxacillin is indicated for Used in the treatment of resistant staphylococci infections. Oxacillin pharmacodynamics: Oxacillin is a penicillin beta-lactam antibiotic used in the treatment of bacterial infections caused by susceptible, usually gram-positive, organisms. The name "penicillin" can either refer to several variants of penicillin available, or to the group of antibiotics derived from the penicillins. Oxacillin has in vitro activity against gram-positive and gram-negative aerobic and anaerobic bacteria. The bactericidal activity of Oxacillin results from the inhibition of cell wall synthesis and is mediated through Oxacillin binding to penicillin binding proteins (PBPs). Oxacillin is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, and cephalosporinases and extended spectrum beta-lactamases. The mechanism of action of Oxacillin is that it By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, Oxacillin inhibits the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins; it is possible that Oxacillin interferes with an autolysin inhibitor. No absorption information is available for Oxacillin. No volume of distribution information is available for Oxacillin. Oxacillin is 94. 2 +/- 2. 1% (binds to serum protein, mainly albumin) bound to plasma proteins. No metabolism information is available for Oxacillin. Oxacillin is eliminated via Oxacillin Sodium is rapidly excreted as unchanged drug in the urine by glomerular filtration and active tubular secretion. The half-life of Oxacillin is 20 to 30 minutes. No clearance information is available for Oxacillin. No toxicity information is available for Oxacillin. Brand names of Oxacillin include No brand names available. No synonyms are available for Oxacillin. Oxacilina Oxacillin Oxacilline Oxacillinum Oxazocillin Oxazocilline Acetylsalicylic acid summary: It is Summary not found. Oxacillin summary: It is Oxacillin is a penicillin antibiotic used to treat a number of susceptible bacterial infections. Answer: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects.

Acetylsalicylic acid

Drug A is Alteplase. Drug B is Procarbazine. The severity of the interaction is moderate. The risk or severity of bleeding and hemorrhage can be increased when Procarbazine is combined with Alteplase. It has been reported that concomitant administration of anticoagulant agents and antidepressants that increase serotonin levels is associated with an increase in hemorrhage. This interaction is due to the inhibition of serotonin reuptake in platelets which produces a reduction of serotonin to even 1% of the normal quantity. Serotonin is very important for the aggregation of platelets and the lack of serotonin does not allow the normal aggregation process of the platelets. Bleeding and hemorrhage are frequent adverse events associated with anticoagulants. Alteplase is indicated for Alteplase is indicated for the treatment of acute ischemic stroke (AIS) and for use in acute myocardial infarction (AMI) for the reduction of mortality and incidence of heart failure. Alteplase is also indicated for the lysis of acute massive pulmonary embolism, defined as acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments, and acute pulmonary emboli accompanied by unstable hemodynamics. Procarbazine is indicated for use with other anticancer drugs for the treatment of stage III and stage IV Hodgkin's disease. Alteplase pharmacodynamics: Alteplase binds to fibrin and plasminogen. Alteplase specificity for fibrin is achieved thanks to its high affinity for lysine residues. Also, it can bind plasminogen via loop structures called kringles, stabilized by three disulphide linkages similar to the ones in plasminogen. The specificity of alteplase for plasminogen bound to fibrin allows this drug to act in a clot- or fibrin-specific manner, leading to low concentrations of circulating plasmin and a lower risk of hemorrhagic transformation. In patients with acute myocardial infarction, alteplase reduces fibrinogen levels 3 to 6 hours after treatment. In patients with acute ischemic stroke, patients treated with alteplase have a significantly higher resolution of hyperdense artery sign, a marker of clot formation in the proximal middle cerebral artery, compared to those treated with placebo. The use of alteplase increases the risk of bleeding and thromboembolic events. Rare cases of cholesterol embolism have also been reported. Procarbazine pharmacodynamics: Procarbazine is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Procarbazine is cell-phase specific for the S phase of cell division. The mechanism of action of Alteplase is that it Alteplase is a recombinant tissue plasminogen activator (rt-PA) that converts plasminogen to plasmin in a fibrin-dependent process. In the absence of fibrin, alteplase converts a limited amount of plasminogen. However, in the presence of fibrin clots, alteplase binds to fibrin and cleaves the arginine-valine bond at positions 560 and 561 of plasminogen, converting it into its active form, plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus and promotes clot dissolution. Alteplase initiates local fibrinolysis with limited systemic proteolysis. The mechanism of action of Procarbazine is that it The precise mode of cytotoxic action of procarbazine has not been clearly defined. There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis. Studies have suggested that procarbazine may inhibit transmethylation of methyl groups of methionine into t-RNA. The absence of functional t-RNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the auto-oxidation of the drug, may attack protein sulfhydryl groups contained in residual protein which is tightly bound to DNA. Alteplase absorption: Healthy volunteers with a baseline endogenous tissue plasminogen activator (t-PA) of 3. 3 ng/ml had a 290-fold increase in baseline concentrations after receiving alteplase at an infusion rate of 0. 25 mg/kg for 30 min; with an infusion rate of 0. 5 mg/kg, a 550-fold increase was observed. Acute myocardial infarction patients (n=12) given 10 mg of alteplase in a 2-minute infusion reached a peak plasma concentration of 3310 ng/ml. This was followed by 50 mg of alteplase in 1 h and 30 mg in 1. 5 h, resulting in steady-state plasma levels of 2210 ng/ml and 930 ng/ml, respectively. Procarbazine absorption: Procarbazine is rapidly and completely absorbed. The volume of distribution of Alteplase is The initial volume of distribution approximates plasma volume. The average volume of distribution of the central compartment goes from 3. 9 to 4. 3 L, and the volume of distribution at steady state goes from 7. 2 to 12 L. No volume of distribution information is available for Procarbazine. Alteplase is Not available. bound to plasma proteins. No protein binding information is available for Procarbazine. Alteplase metabolism: Alteplase is mainly metabolized by the liver. The carbohydrate and polypeptide domains of alteplase interact with hepatic glycoprotein receptors, leading to receptor-mediated endocytosis. In vivo studies suggest that alteplase follows zero-order kinetics, meaning that its metabolism is saturable at higher plasma concentrations. Procarbazine metabolism: Procarbazine is metabolized primarily in the liver and kidneys. The drug appears to be auto-oxidized to the azo derivative with the release of hydrogen peroxide. The azo derivative isomerizes to the hydrazone, and following hydrolysis splits into a benzylaldehyde derivative and methylhydrazine. The methylhydrazine is further degraded to CO 2 and CH 4 and possibly hydrazine, whereas the aldehyde is oxidized to N-isopropylterephthalamic acid, which is excreted in the urine. Alteplase is eliminated via In healthy volunteers, more than 80% of alteplase is eliminated through urine 18 hours after administration. Procarbazine is eliminated via No route of elimination available. The half-life of Alteplase is Alteplase has an initial half-life of less than 5 minutes in patients with acute myocardial infarction (AMI). The dominant initial plasma half-life of the 3-hour and the accelerated regimens for AMI are similar. The half-life of Procarbazine is 10 minutes. The clearance of Alteplase is Alteplase has a plasma clearance between 380 and 570 mL/min. No clearance information is available for Procarbazine. Alteplase toxicity includes Toxicity information regarding alteplase is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as risk of bleeding and thromboembolic events. Symptomatic and supportive measures are recommended. The carcinogenic potential of alteplase or its effect on fertility have not been evaluated. In vivo studies evaluating tumorigenicity and in vitro studies evaluating mutagenicity were negative. It has been estimated that the acute oral and dermal toxicity of alteplase is above 5,000 mg/kg. Procarbazine toxicity includes LD 50 =785 mg/kg (orally in rats). Brand names of Alteplase include Activase, Cathflo, Cathflo Activase. Brand names of Procarbazine include Matulane. No synonyms are available for Alteplase. No synonyms are available for Procarbazine. Procarbazina Procarbazine Procarbazinum Alteplase summary: It is Alteplase is a recombinant form of human tissue plasminogen activator used in the emergency treatment of myocardial infarction, ischemic stroke, and pulmonary emboli. Procarbazine summary: It is Procarbazine is an antineoplastic agent indicated for the treatment of stage III and stage IV Hodgkin's disease in combination with other chemotherapeutic agents. Answer: It has been reported that concomitant administration of anticoagulant agents and antidepressants that increase serotonin levels is associated with an increase in hemorrhage. This interaction is due to the inhibition of serotonin reuptake in platelets which produces a reduction of serotonin to even 1% of the normal quantity. Serotonin is very important for the aggregation of platelets and the lack of serotonin does not allow the normal aggregation process of the platelets. Bleeding and hemorrhage are frequent adverse events associated with anticoagulants.

Alteplase

Drug A is Abacavir. Drug B is Ixazomib. The severity of the interaction is minor. Abacavir may decrease the excretion rate of Ixazomib which could result in a higher serum level. The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes, they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs. Abacavir is indicated for Abacavir is indicated in combination with other anti-retroviral agents for the treatment of HIV-1 infection. It is available in a combination product alongside dolutegravir and lamivudine for the treatment of adult and pediatric patients with HIV-1 who weigh ≥10 kg. Ixazomib is indicated for Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Abacavir pharmacodynamics: Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Abacavir is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The concentration of drug necessary to effect viral replication by 50 percent (EC50) ranged from 3. 7 to 5. 8 μM (1 μM = 0. 28 mcg/mL) and 0. 07 to 1. 0 μM against HIV-1IIIB and HIV-1BaL, respectively, and was 0. 26 ± 0. 18 μM against 8 clinical isolates. Abacavir had synergistic activity in cell culture in combination with the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, and the protease inhibitor (PI) amprenavir; and additive activity in combination with the NRTIs didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine. Ixazomib pharmacodynamics: In vitro studies have shown ixazomib to induce apoptosis in multiple myeloma cells sensitive or resistant to other conventional therapies. In mouse xenograft models, ixazomib induced tumor growth inhibition. The mechanism of action of Abacavir is that it Abacavir is a carbocyclic synthetic nucleoside analogue and an antiviral agent. Intracellularly, abacavir is converted by cellular enzymes to the active metabolite carbovir triphosphate, an analogue of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Viral DNA growth is terminated because the incorporated nucleotide lacks a 3'-OH group, which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation. The mechanism of action of Ixazomib is that it Ixazomib is an N-capped dipeptidyl leucine boronic acid which reversibly inhibits the CT-L proteolytic (β5) site of the 20S proteasome. At higher concentrations, ixazomib also seems to inhibit the proteolytic β1 and β2 subunits and to induce accumulation of ubiquitinated proteins. Abacavir absorption: Rapid and extensive after oral administration (83% bioavailability, tablet). When a 300 mg tablet is given twice daily to subjects, the peak plasma concentration (Cmax) was 3. 0 ± 0. 89 mcg/mL and the area under the curve (AUC 0-12 hours) was 6. 02 ± 1. 73 mcg•hr/mL. Ixazomib absorption: After oral administration, the time to reach maximum concentration in plasma was 1 hour. The mean absolute oral bioavailability is 58%. The volume of distribution of Abacavir is 0. 86 ± 0. 15 L/kg [IV administration]. The volume of distribution of Ixazomib is The steady-state volume of distribution is 543 L. Abacavir is Moderate (approximately 50%). Binding of abacavir to plasma protein was independent of concentration. bound to plasma proteins. Ixazomib is 99% bound to plasma proteins. Abacavir metabolism: Hepatic, by alcohol dehydrogenase and glucuronosyltransferase to a 5′-carboxylic acid metabolite and 5′-glucuronide metabolite, respectively. These metabolites have no antiviral activity. Abacavir is not significantly metabolized by cytochrome P450 enzymes. Ixazomib metabolism: Metabolism of ixazomib is expected to be by CYP and non-CYP pathways, with no predominant CYP isozyme contribution. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (<1%). Abacavir is eliminated via Elimination of abacavir was quantified in a mass balance study following administration of a 600-mg dose of 14C-abacavir: 99% of the radioactivity was recovered, 1. 2% was excreted in the urine as abacavir, 30% as the 5′-carboxylic acid metabolite, 36% as the 5′-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose. Renal excretion of unchanged abacavir is a minor route of elimination in humans. Ixazomib is eliminated via 62% in urine and 22% in feces. The half-life of Abacavir is 1. 54 ± 0. 63 hours. The half-life of Ixazomib is Terminal half-life is 9. 5 days. The clearance of Abacavir is 0. 80 ± 0. 24 L/hr/kg [asymptomatic, HIV-1-infected adult patients receiving single (IV dose of 150 mg]. No clearance information is available for Ixazomib. Abacavir toxicity includes Some myocardial degeneration has been noticed in rats and mice. The most commonly reported adverse reactions of at least moderate intensity (incidence ≥10%) in adult HIV-1 clinical trials were nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders. Serious hypersensitivity reactions have been associated with abacavir which has been strongly linked to the presence of the HLA-B*57:01 allele. This reaction manifests itself in patients within the first 6 weeks of treatment. Patients should be tested for the presence of this allele as recommended by the U. S Food and Drug Administration (FDA). Ixazomib toxicity includes Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in <1% of patients. Ixazomib can cause fetal harm when administered to pregnant women, and therefore it should also be advised to women of reproductive age to avoid becoming pregnant on ixazomib. Brand names of Abacavir include Epzicom, Kivexa, Triumeq, Trizivir, Ziagen. Brand names of Ixazomib include Ninlaro. No synonyms are available for Abacavir. ABC No synonyms are available for Ixazomib. Abacavir summary: It is Abacavir is an antiviral nucleoside reverse transcriptase inhibitor used in combination with other antiretrovirals for the treatment of HIV. Ixazomib summary: It is Ixazomib is a monoclonal antibody used with other medications to treat multiple myeloma in patients who have received one other therapy already. Answer: The renal excretion of drugs is the overall result of a combination of kidney processes that include glomerular filtration, passive diffusion, tubular secretion, and tubular reabsorption. Since two of these mechanisms - tubular secretion and reabsorption - are saturable processes , they are consequently susceptible to competition between multiple substrates excreted by the kidneys. If two or more medications that are mainly renally excreted are co-administered, they may compete for renal elimination; there is a large likelihood that one agent may "out-compete" or saturate the renal excretion mechanisms before the other concomitantly administered agent(s) are excreted. As a result, the elimination of these other concurrently administered agents may be inhibited or otherwise delayed, which could lead to increases in their serum concentrations and the risk, incidence, and/or severity of adverse effects associated with the exposure to such drugs.

Abacavir

Drug A is Denosumab. Drug B is Eftrenonacog alfa. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Denosumab is combined with Eftrenonacog alfa. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Denosumab is indicated for Denosumab under the brand name Prolia is indicated as a treatment for osteoporosis in menopausal women or men and glucocorticoid-induced osteoporosis in men and women at high risk of fracture. It is also used to increase bone mass in men at high risk for fractures receiving androgen deprivation therapy for nonmetastatic prostate cancer or women at high risk for fractures receiving adjuvant aromatase inhibitor therapy for breast cancer. Denosumab under the brand name Xgeva is indicated to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors and to treat giant cell tumors of bone in adults and skeletally mature adolescents and hypercalcemia of malignancy refractory to bisphosphonate therapy. Eftrenonacog alfa is indicated for Indicated for the treatment and prophylaxis of bleeding in patients of all age with haemophilia B (congenital factor IX deficiency). Denosumab pharmacodynamics: In clinical studies, treatment with 60 mg of denosumab resulted in a reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0. 049 ng/mL) in 39% to 68% of patients 1 to 3 months after dosing of denosumab. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of denosumab on bone remodelling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by denosumab was similar to that observed in patients initiating denosumab treatment. Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i. e., osteocalcin and procollagen type 1 N-terminal peptide [P1NP]) were observed starting 1 month after the first dose of denosumab. After discontinuation of denosumab therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months. In patients with breast cancer and bone metastases, the median reduction in urinary N-terminal telopeptide corrected for creatinine (uNTx/Cr) was 82% within 1 week following initiation of denosumab 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 denosumab-treated patients. In a phase 3 study of patients with newly diagnosed multiple myeloma who received subcutaneous doses of denosumab 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing. Eftrenonacog alfa pharmacodynamics: In two multinational, phase III studies in previously treated children, adolescents and adults with severe haemophilia B, eftrenonacog alfa prophylaxis resulted in low median annualized bleeding rates (ABRs), and was associated with reductions in median weekly factor consumption and dosing frequency compared with pre-study FIX regimens. The extension of those studies demonstrated effectiveness in the treatment of bleeding episodes and when used in the perioperative setting in all age groups. In animal models, a single intravenous dose of eftrenonacog alfa displayed half values approximately three- to four-fold longer than those seen with recombinant FIX. The mechanism of action of Denosumab is that it Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. The mechanism of action of Eftrenonacog alfa is that it The coagulation protein factor IX (FIX) is a vitamin K-dependent coagulation factor and one of the critical serine proteases involved in the coagulation cascade. Upon activation by factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway, factor IX, in combination with factor VIII, activates factor X. Activated factor X mediates the conversion of prothrombin to thrombin which sequentially leads to thrombin converting fibrinogen into fibrin. A blood clot is then formed. With a mutation in the gene encoding the coagulation protein factor IX (FIX), patients with hemophilia B have factor IX deficiency and are at high risk for recurrent bleeding episodes. Eftrenonacog alfa is composed of a single molecule of recombinant FIX (rFIX) covalently fused to the dimeric Fc domain of immunoglobulin (Ig) G1 (rFIXFc). It serves as a replacement therapy to increase the plasma levels of factor IX thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies. The Fc region of human immunoglobulin G1 binds with the neonatal Fc receptor which is expressed throughout life as part of a naturally occurring pathway that protects immunoglobulins from lysosomal degradation by cycling these proteins back into circulation, resulting in their long plasma half-life. The binding of eftrenonacog alfa to the neonatal Fc receptor delays degradation and recycles the fusion protein back into circulation for increased plasma half life and prolonged therapeutic action. Denosumab absorption: In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered denosumab dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (Cmax ) was 6. 75 mcg/mL (standard deviation [SD] = 1. 89 mcg/mL). The median time to maximum denosumab concentration (Tmax ) was 10 days (range: 3 to 21 days). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg⋅day/mL (SD = 101 mcg⋅day/mL. No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months. Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years). After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) Cmax values in the serum and seminal fluid samples were 6170 (± 2070) and 100 (± 81. 9) ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels. The median (range) Tmax values in the serum and seminal fluid samples were 8. 0 (7. 9 to 21) and 21 (8. 0 to 49) days, respectively. Among the subjects, the highest denosumab concentration in the seminal fluid was 301 ng/mL at 22 days post-dose. On the first day of measurement (10 days post-dose), nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post-dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) seminal fluid concentration of 21. 1 (± 36. 5) ng/mL across all subjects (n = 12). In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach a steady state by month 6. In patients with giant cell tumor of bone, after administration of subcutaneous doses of 120 mg once every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day 8, 15, and one month after the first dose were 19. 0 (± 24. 1), 31. 6 (± 27. 3), 36. 4 (± 20. 6) mcg/mL,. respectively. Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23. 4 (± 12. 1) mcg/mL. Eftrenonacog alfa absorption: Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean peak plasma concentration (Cmax) was 46. 10 IU/dL. The mean area under the FIX activity time curve (AUC) was 31. 58 Uxh/dL per IU/kg. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean AUC ranged from 22. 71 to 29. 50 Uxh/dL per IU/kg. The volume of distribution of Denosumab is The central volume of distribution and volume of distribution at steady-state were calculated to be 2. 49 L/66 kg and 3. 5-7 L respectively. The volume of distribution of Eftrenonacog alfa is Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean volume of distribution at steady-state (Vss) was 303. 4 mL/kg. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean Vss ranged from 289 to 365. 1 mL/kg. Denosumab is No information is available on the protein binding of denosumab. bound to plasma proteins. No protein binding information is available for Eftrenonacog alfa. Denosumab metabolism: No information is available on the metabolism of denosumab. Eftrenonacog alfa metabolism: The Fc domain of eftrenonacog alfa is expected to undergo lysosomal degradation while the remaining recombinant FIX (rFIX) portion is expected to be metabolized by the same pathway as endogenous factor IX. Denosumab is eliminated via As an antibody, denosumab is likely cleared by the reticuloendothelial system with minimal renal filtration and excretion. Eftrenonacog alfa is eliminated via Eftrenonacog alfa is expected to undergo renal clearance. The half-life of Denosumab is After Cmax, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25. 4 days (SD = 8. 5 days; n = 46). The half-life of Eftrenonacog alfa is Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean terminal half life (t1/2) was 77. 6 hours. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, the mean t1/2 ranged from 66. 49 to 82. 22 hours. The clearance of Denosumab is No information is available on the clearance of denosumab. The clearance of Eftrenonacog alfa is Following administration of a single intravenous dose of 50 IU/kg of eftrenonacog alfa in patients ≥19 years of age with hemophilia B, the mean clearance (CL) was 3. 17 mL/h/kg. In pediatric and adolescent patients (< 18 years of age) receiving the same dose, mean CL ranged from 3. 390 to 4. 365 mL/h/kg. Denosumab toxicity includes Denosumab is contraindicated for use in pregnant women because it may cause harm to a fetus. There are insufficient data with denosumab use in pregnant women to inform any drug-associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes,. abnormal bone growth, and decreased neonatal growth. In clinical trials, hypercalcemia has been reported in pediatric patients with osteogenesis imperfect treated with denosumab products, including Prolia. Some cases required hospitalization and were complicated by acute renal injury. Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years. The carcinogenic and genotoxic potential of denosumab has not been evaluated in long-term animal studies. Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg). Eftrenonacog alfa toxicity includes Based on findings from a rabbit thrombogenicity test and rat or monkey repeated-dose toxicity studies, eftrenonacog alfa displays no special hazards for humans. Studies to investigate the genotoxicity, carcinogenicity, toxicity to reproduction or embryo-foetal development have not been conducted. Eftrenonacog alfa has shown to cross the placenta in small amounts according to a mouse placental transfer study. Brand names of Denosumab include Prolia, Xgeva. Brand names of Eftrenonacog alfa include Alprolix. No synonyms are available for Denosumab. No synonyms are available for Eftrenonacog alfa. Denosumab summary: It is Denosumab is a RANK ligand (RANKL) inhibitor used for the management of osteoporosis in patients at high risk for bone fractures. Eftrenonacog alfa summary: It is Eftrenonacog alfa is a recombinant Factor IX used to treat and prevent bleeding in hemophilia B. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Denosumab

Drug A is Acarbose. Drug B is Tolazamide. The severity of the interaction is moderate. The risk or severity of hypoglycemia can be increased when Acarbose is combined with Tolazamide. Both the subject and the affected drug are associated with hypoglycemia, either by design (i. e. antihyperglycemics in diabetes) or as part of an adverse effect profile. The use of multiple medications that can lower blood glucose may lead to an additive blood glucose-lowering effect and subsequent symptomatic hypoglycemia. Acarbose is indicated for Acarbose is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Tolazamide is indicated for use as an adjunct to diet to lower the blood glucose in patients with non-insulin dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone. Acarbose pharmacodynamics: Acarbose is a complex oligosaccharide that competitively inhibits the ability of brush-border alpha-glucosidase enzymes to break down ingested carbohydrates into absorbable monosaccharides, reducing carbohydrate absorption and subsequent postprandial insulin levels. Acarbose requires the co-administration of carbohydrates in order to exert its therapeutic effect, and as such should be taken with the first bite of a meal three times daily. Given its mechanism of action, acarbose in isolation poses little risk of contributing to hypoglycemia - this risk is more pronounced, however, when acarbose is used in conjunction with other antidiabetic therapies (e. g. sulfonylureas, insulin). Patients maintained on acarbose in addition to other antidiabetic agents should be aware of the symptoms and risks of hypoglycemia and how to treat hypoglycemic episodes. There have been rare post-marketing reports of the development of pneumatosis cystoides intestinalis following treatment with alpha-glucosidase inhibitors - patients experiencing significant diarrhea/constipation, mucus discharge, and/or rectal bleeding should be investigated and, if pneumatosis cystoides intestinalis is suspected, should discontinue therapy. Tolazamide pharmacodynamics: Tolazamide is an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide, may become unresponsive or poorly responsive over time. Alternatively, tolazamide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance. The mechanism of action of Acarbose is that it Alpha-glucosidase enzymes are located in the brush-border of the intestinal mucosa and serve to metabolize oligo-, tri-, and disaccharides (e. g. sucrose) into smaller monosaccharides (e. g. glucose, fructose) which are more readily absorbed. These work in conjunction with pancreatic alpha-amylase, an enzyme found in the intestinal lumen that hydrolyzes complex starches to oligosaccharides. Acarbose is a complex oligosaccharide that competitively and reversibly inhibits both pancreatic alpha-amylase and membrane-bound alpha-glucosidases - of the alpha-glucosidases, inhibitory potency appears to follow a rank order of glucoamylase > sucrase > maltase > isomaltase. By preventing the metabolism and subsequent absorption of dietary carbohydrates, acarbose reduces postprandial blood glucose and insulin levels. The mechanism of action of Tolazamide is that it Sulfonylureas likely bind to ATP-sensitive potassium-channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. Acarbose absorption: The oral bioavailability of acarbose is extremely minimal, with less than 1-2% of orally administered parent drug reaching the systemic circulation. Despite this, approximately 35% of the total radioactivity from a radiolabeled and orally administered dose of acarbose reaches the systemic circulation, with peak plasma radioactivity occurring 14-24 hours after dosing - this delay is likely reflective of metabolite absorption rather than absorption of the parent drug. As acarbose is intended to work within the gut, its minimal degree of oral bioavailability is therapeutically desirable. Tolazamide absorption: Rapidly and well absorbed from the gastrointestinal tract. No volume of distribution information is available for Acarbose. No volume of distribution information is available for Tolazamide. Acarbose is As only 1-2% of an orally administered dose is absorbed into the circulation, acarbose is unlikely to be subject to clinically relevant protein binding. bound to plasma proteins. No protein binding information is available for Tolazamide. Acarbose metabolism: Acarbose is extensively metabolized within the gastrointestinal tract, primarily by intestinal bacteria and to a lesser extent by digestive enzymes, into at least 13 identified metabolites. Approximately 1/3 of these metabolites are absorbed into the circulation where they are subsequently renally excreted. The major metabolites appear to be methyl, sulfate, and glucuronide conjugates of 4-methylpyrogallol. Only one metabolite - resulting from the cleavage of a glucose molecule from acarbose - has been identified as having alpha-glucosidase inhibitory activity. Tolazamide metabolism: Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0 to 70%. Acarbose is eliminated via Roughly half of an orally administered dose is excreted in the feces within 96 hours of administration. What little drug material is absorbed into the systemic circulation (approximately 34% of an orally administered dose) is excreted primarily by the kidneys, suggesting renal excretion would be a significant route of elimination if the parent drug was more readily absorbed - this is further supported by data in which approximately 89% of an intravenously administered dose of acarbose was excreted in the urine as active drug (in comparison to <2% following oral administration) within 48 hours. Tolazamide is eliminated via Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0% to 70%. They are excreted principally in the urine. The half-life of Acarbose is In healthy volunteers, the plasma elimination half-life of acarbose is approximately 2 hours. The half-life of Tolazamide is The average biological half-life of the drug is 7 hours. No clearance information is available for Acarbose. No clearance information is available for Tolazamide. Acarbose toxicity includes The symptoms of acarbose overdose are likely to be consistent with its adverse effect profile and may therefore include significant gastrointestinal (GI) symptoms (flatulence, distension, etc), although an overdose on an empty stomach (i. e. when not co-administered with food) is less likely to result in these GI symptoms. In the event of an overdose, patients should be instructed to avoid carbohydrate-containing foods for 4-6 hours following administration as these can precipitate the aforementioned GI symptoms. Tolazamide toxicity includes Overdosage of sulfonylureas can produce hypoglycemia. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. Brand names of Acarbose include Precose. Brand names of Tolazamide include Tolinase. No synonyms are available for Acarbose. No synonyms are available for Tolazamide. Tolazamida Tolazamide Tolazamidum Acarbose summary: It is Acarbose is an alpha-glucosidase inhibitor used in adjunctly with diet and exercise for the management of glycemic control in patients with type 2 diabetes mellitus. Tolazamide summary: It is Tolazamide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus. Answer: Both the subject and the affected drug are associated with hypoglycemia, either by design (i. e. antihyperglycemics in diabetes) or as part of an adverse effect profile. The use of multiple medications that can lower blood glucose may lead to an additive blood glucose-lowering effect and subsequent symptomatic hypoglycemia.

Acarbose

Drug A is Protein C. Drug B is Cyclophosphamide. The severity of the interaction is minor. The risk or severity of bleeding can be increased when Protein C is combined with Cyclophosphamide. Myelosuppressive agents can cause a number of blood dyscrasias, including neutropenia and thrombocytopenia - the latter, referring to a decrease in the number of circulating platelets, can result in an increased risk of bleeding. Coadministration of myelosuppressives with other blood thinning agents may result in an increased risk of abnormal bleeding. Protein C is indicated for Protein C concentrate is indicated for pediatric and adult patients with severe congenital protein C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. It is also found as a component of some prothrombin complex concentrate (i. e. Factor IX Complex (Human) ) formulations, such as Kcentra. Cyclophosphamide is indicated for Cyclophosphamide is indicated for the treatment of malignant lymphomas, multiple myeloma, leukemias, mycosis fungoides (advanced disease), neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma, and carcinoma of the breast. It is also indicated for the treatment of biopsy-proven minimal change nephrotic syndrome in pediatric patients. Protein C pharmacodynamics: In clinical studies, the intravenous administration of Protein C Concentrate demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of APC. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications. Cyclophosphamide pharmacodynamics: Cyclophosphamide is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. The mechanism of action of Protein C is that it Protein C is an endogenously occurring plasma protein that plays a key role within the coagulation cascade. Also known as blood coagulation factor XIV, Protein C is a zymogen, or enzyme precursor, of a vitamin K-dependent anticoagulant glycoprotein (serine protease) that is synthesized in the liver. It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to Activated Protein C (APC). Once in its activated form, APC functions as a serine protease with potent anticoagulant effects, especially in the presence of its cofactor protein S. APC exerts its effect by inactivating essential components of the coagulation cascade (specifically factors V and VIII), which leads to a decrease in thrombin formation, and therefore a reduction in clot formation. The mechanism of action of Cyclophosphamide is that it Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. Protein C absorption: Cmax = 110 IU/dL. Tmax = 0. 50 hr Cyclophosphamide absorption: After oral administration, peak concentrations occur at one hour. The volume of distribution of Protein C is Volume of distribution at steady state = 0. 74 dL/kg. The volume of distribution of Cyclophosphamide is 30-50 L. No protein binding information is available for Protein C. Cyclophosphamide is 20% of cyclophosphamide is protein bound with no dose dependent changes. Some metabolites are protein bound to an extent greater than 60%. bound to plasma proteins. No metabolism information is available for Protein C. Cyclophosphamide metabolism: Metabolism and activation occurs at the liver. 75% of the drug is activated by cytochrome P450 isoforms, CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19. The CYP2B6 isoform is the enzyme with the highest 4-hydroxylase activity. Cyclophosphamide undergoes activation to eventually form active metabolites, phosphoramide mustard and acrolein. Cyclophosphamide appears to induce its own metabolism which results in an overall increase in clearance, increased formation of 4-hydroxyl metabolites, and shortened t1/2 values following repeated administration. Protein C is eliminated via No route of elimination available. Cyclophosphamide is eliminated via Cyclophosphamide is eliminated primarily in the form of metabolites. 10-20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration. The half-life of Protein C is Initial half life = 7. 8 hr. Terminal half life = 9. 9 hr The half-life of Cyclophosphamide is 3-12 hours. The clearance of Protein C is CL = 0. 0533 dL/kg/h. The clearance of Cyclophosphamide is Total body clearance = 63 ± 7. 6 L/kg. No toxicity information is available for Protein C. Cyclophosphamide toxicity includes Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. Brand names of Protein C include Balfaxar, Beriplex, Ceprotin, Kcentra, Octaplex. Brand names of Cyclophosphamide include Procytox. No synonyms are available for Protein C. No synonyms are available for Cyclophosphamide. (RS)-Cyclophosphamide Ciclofosfamida Ciclofosfamide Cyclophosphamid Cyclophosphamide Cyclophosphamidum Cytophosphane Protein C summary: It is Protein C is a medication used to treat protein C deficiency leading to purpura fulminans or coumarin-induced skin necrosis. Cyclophosphamide summary: It is Cyclophosphamide is a nitrogen mustard used to treat lymphomas, myelomas, leukemia, mycosis fungoides, neuroblastoma, ovarian adenocarcinoma, retinoblastoma, and breast carcinoma. Answer: Myelosuppressive agents can cause a number of blood dyscrasias, including neutropenia and thrombocytopenia - the latter, referring to a decrease in the number of circulating platelets, can result in an increased risk of bleeding. Coadministration of myelosuppressives with other blood thinning agents may result in an increased risk of abnormal bleeding.

Protein C

Drug A is Aldesleukin. Drug B is Interferon alfa-2a. The severity of the interaction is moderate. The risk or severity of adverse effects can be increased when Interferon alfa-2a is combined with Aldesleukin. Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis appear to be increased in patients receiving alfa interferon and aldesleukin concomitantly. Exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders has also been observed following the concurrent use of alfa interferon and aldesleukin, including crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome. The mechanism of action of this interaction has not yet been formally elucidated, although some proposed models include additive severe cardiac and renal toxicities elicited by both alfa interferon and aldesleukin individually, and/or the possibility of the combination use of alfa interferon and aldesleukin to cause myocardial damage, interstitial edema, myocyte degeneration, and/or mitochondria swelling. Nevertheless, other studies have also demonstrated that the combined use of alfa interferon and aldesleukin do not directly damage myocytes at all. Aldesleukin is indicated for treatment of adults with metastatic renal cell carcinoma. Interferon alfa-2a is indicated for the treatment of chronic hepatitis C, hairy cell leukemia, AIDS-related Kaposi's sarcoma, and chronic myelogenous leukemia. Also for the treatment of oral warts arising from HIV infection. Aldesleukin pharmacodynamics: Used to treat renal cell carcinoma, Aldesleukin induces the enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, the enhancement of lymphocyte cytotoxicity, the induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and the induction of interferon-gamma production. IL-2 is normally produced by the body, secreted by T cells, and stimulates growth and differentiation of T cell response. It can be used in immunotherapy to treat cancer. It enhances the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor. Interferon alfa-2a pharmacodynamics: Upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Interferon alpha also induce the synthesis of several key antiviral mediators, including 2'-5' oligoadenylate synthetase (2'-5' A synthetase) and protein kinase R. The mechanism of action of Aldesleukin is that it Aldesleukin binds to the IL-2 receptor which leads to heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. These events stimulate growth and differentiation of T cells. The mechanism of action of Interferon alfa-2a is that it Interferon alpha binds to type I interferon receptors (IFNAR1 and IFNAR2c) which, upon dimerization, activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription)which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon alpha binds less stably to type I interferon receptors than interferon beta. No absorption information is available for Aldesleukin. Interferon alfa-2a absorption: Absorption is high (greater than 80%) when administered intramuscularly or subcutaneously. The volume of distribution of Aldesleukin is 0. 18 l/kg. The volume of distribution of Interferon alfa-2a is 0. 223 to 0. 748 L/kg [healthy people]. No protein binding information is available for Aldesleukin. No protein binding information is available for Interferon alfa-2a. No metabolism information is available for Aldesleukin. No metabolism information is available for Interferon alfa-2a. Aldesleukin is eliminated via The pharmacokinetic profile of Proleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Following the initial rapid organ distribution, the primary route of clearance of circulating proleukin is the kidney. Greater than 80% of the amount of Proleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. Interferon alfa-2a is eliminated via Alpha-interferons are totally filtered through the glomeruli and undergo rapid proteolytic degradation during tubular reabsorption, rendering a negligible reappearance of intact alfa interferon in the systemic circulation. The half-life of Aldesleukin is 13 min-85 min. The half-life of Interferon alfa-2a is The IM half-life of interferon alfa-2a is 6 hours to 8 hours; the half-life for IV infusion is 3. 7 hours to 8. 5 hours (mean 5. 1 hours). No clearance information is available for Aldesleukin. The clearance of Interferon alfa-2a is 2. 14 - 3. 62 mL/min/kg [healthy]. No toxicity information is available for Aldesleukin. Interferon alfa-2a toxicity includes Interferon alfa-2 may cause serious adverse effects such as anemia; autoimmune diseases, including vasculitis, arthritis, hemolytic anemia, and erythematosus syndrome; cardiotoxicity; hepatotoxicity; hyperthyroidism or hypothyroidism; transient ischemic attacks; leukopenia; neurotoxicity; peripheral neuropathy; and thrombocytopenia. Some lesser side effects that may not need medical attention include blurred vision, change in taste or metallic taste, cold sores or stomatitis, diarrhea, dizziness, dry mouth, dry skin or itching, flu-like syndrome, increased sweating, leg cramps, loss of appetite, nausea or vomiting, skin rash, unusual tiredness, weight loss, and partial loss of hair. Brand names of Aldesleukin include Proleukin. Brand names of Interferon alfa-2a include No brand names available. No synonyms are available for Aldesleukin. No synonyms are available for Interferon alfa-2a. Interferon alfa-2a (genetical recombination) Interferon alfa-2a (recombinant) Interferon alfa-2a, recombinant Interferon alfa-2a,recombinant Interferon alpha-2a Interferon-alfa-2a Recombinant human interferon alfa-2a Recombinant human interferon-alfa-2a Aldesleukin summary: It is Aldesleukin is a recombinant analog of interleukin-2 used to induce an adaptive immune response in the treatment of renal cell carcinoma. Interferon alfa-2a summary: It is Interferon alfa-2a is a form of recombinant human interferon used to stimulate the innate antiviral response in the treatment of hepatitis B and C viruses. Answer: Myocardial injury, including myocardial infarction, myocarditis, ventricular hypokinesia, and severe rhabdomyolysis appear to be increased in patients receiving alfa interferon and aldesleukin concomitantly. Exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders has also been observed following the concurrent use of alfa interferon and aldesleukin, including crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome. The mechanism of action of this interaction has not yet been formally elucidated, although some proposed models include additive severe cardiac and renal toxicities elicited by both alfa interferon and aldesleukin individually , and/or the possibility of the combination use of alfa interferon and aldesleukin to cause myocardial damage, interstitial edema, myocyte degeneration, and/or mitochondria swelling. Nevertheless, other studies have also demonstrated that the combined use of alfa interferon and aldesleukin do not directly damage myocytes at all.

Aldesleukin

Drug A is Adalimumab. Drug B is Typhoid vaccine. The severity of the interaction is moderate. The therapeutic efficacy of Typhoid vaccine can be decreased when used in combination with Adalimumab. Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. Adalimumab is indicated for Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. Adalimumab pharmacodynamics: After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. The mechanism of action of Adalimumab is that it Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). Adalimumab absorption: The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4. 7 ± 1. 6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0. 5 to 10. 0 mg/kg following a single intravenous dose. The volume of distribution of Adalimumab is The distribution volume (Vss) ranged from 4. 7 to 6. 0 L following intravenous administration of doses ranging from 0. 25 to 10 mg/kg in RA patients. No protein binding information is available for Adalimumab. No metabolism information is available for Adalimumab. Adalimumab is eliminated via Adalimumab is most likely removed by opsonization via the reticuloendothelial system. The half-life of Adalimumab is The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. The clearance of Adalimumab is The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0. 25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. Adalimumab toxicity includes Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. Brand names of Adalimumab include Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry. No synonyms are available for Adalimumab. Adalimumab summary: It is Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. Typhoid vaccine summary: It is Summary not found. Answer: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent.

Adalimumab

Drug A is Adefovir dipivoxil. Drug B is Mannitol. The severity of the interaction is minor. The risk or severity of nephrotoxicity can be increased when Mannitol is combined with Adefovir dipivoxil. Mannitol infusions can occasionally lead to acute kidney injury. 3 Nephrotoxic agents can also lead to kidney damage. 2,1 Concomitant administration of these medications may potentiate nephrotoxic effects, but the clinical relevance of this interaction is unknown. Adefovir dipivoxil is indicated for Indicated for the treatment of chronic hepatitis B in adult patients with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease; this is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function. Mannitol is indicated for Used for the promotion of diuresis before irreversible renal failure becomes established, the reduction of intracranial pressure, the treatment of cerebral edema, and the promotion of urinary excretion of toxic substances. Mannitol is also indicated as add-on maintenance therapy for improving pulmonary function in cystic fibrosis patients aged 18 and over who have passed the BRONCHITOL tolerance test (BTT). It is recommended that patients take an orally inhaled short-acting bronchodilator 5-15 minutes prior to every inhaled mannitol dose. Adefovir dipivoxil pharmacodynamics: Adefovir dipivoxil a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV). The concentration of adefovir that inhibited 50% of viral DNA synthesis (IC50) in vitro ranged from 0. 2 to 2. 5 μM in HBV transfected human hepatoma cell lines. The combination of adefovir with lamivudine showed additive anti-HBV activity. Mannitol pharmacodynamics: Chemically, mannitol is an alcohol and a sugar, or a polyol; it is similar to xylitol or sorbitol. However, mannitol has a tendency to lose a hydrogen ion in aqueous solutions, which causes the solution to become acidic. For this reason, it is not uncommon to add a substance to adjust its pH, such as sodium bicarbonate. Mannitol is commonly used to increase urine production (diuretic). It is also used to treat or prevent medical conditions that are caused by an increase in body fluids/water (e. g., cerebral edema, glaucoma, kidney failure). Mannitol is frequently given along with other diuretics (e. g., furosemide, chlorothiazide) and/or IV fluid replacement. Inhaled mannitol has the possibility to cause bronchospasm and hemoptysis; the occurrence of either should lead to discontinuation of inhaled mannitol. The mechanism of action of Adefovir dipivoxil is that it Adefovir dipivoxil is a prodrug of adefovir. Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0. 1 μM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1. 18 μM and 0. 97μM, respectively. The mechanism of action of Mannitol is that it Mannitol is an osmotic diuretic that is metabolically inert in humans and occurs naturally, as a sugar or sugar alcohol, in fruits and vegetables. Mannitol elevates blood plasma osmolality, resulting in enhanced flow of water from tissues, including the brain and cerebrospinal fluid, into interstitial fluid and plasma. As a result, cerebral edema, elevated intracranial pressure, and cerebrospinal fluid volume and pressure may be reduced. As a diurectic mannitol induces diuresis because it is not reabsorbed in the renal tubule, thereby increasing the osmolality of the glomerular filtrate, facilitating excretion of water, and inhibiting the renal tubular reabsorption of sodium, chloride, and other solutes. Mannitol promotes the urinary excretion of toxic materials and protects against nephrotoxicity by preventing the concentration of toxic substances in the tubular fluid. As an Antiglaucoma agent mannitol levates blood plasma osmolarity, resulting in enhanced flow of water from the eye into plasma and a consequent reduction in intraocular pressure. As a renal function diagnostic aid mannitol is freely filtered by the glomeruli with less than 10% tubular reabsorption. Therefore, its urinary excretion rate may serve as a measurement of glomerular filtration rate (GFR). The exact mechanism of action of inhaled mannitol in the symptomatic maintenance treatment of cystic fibrosis remains unclear. It is hypothesized that mannitol produces an osmotic gradient across the airway epithelium that draws fluid into the extracellular space and alters the properties of the airway surface mucus layer, allowing easier mucociliary clearance. Adefovir dipivoxil absorption: The approximate oral bioavailability of adefovir from HEPSERA is 59%. When a single oral 10 mg dose is given to chronic hepatitis B patients, the peak plasma concentration (Cmax) of adefovir was 18. 4 ± 6. 26 ng/mL. This occurred between 0. 58 - 4 hours post dose (Tmax). The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70. 0 ng∙h/mL. Food does not affect the exposure of adeforvir. Mannitol absorption: Approximately 7% of ingested mannitol is absorbed during gastrointestinal perfusion in uremic patients. Inhalation of 635 mg of mannitol powder yields a plasma Cmax of 13. 71 μg/mL in 1. 5 hours (Tmax ) and a mean systemic AUC of 73. 15 μg*h/mL. The volume of distribution of Adefovir dipivoxil is 392 ± 75 mL/kg [Vd at steady state, intravenous administration of 1. 0 mg/kg/day]. 352 ± 9 mL/kg [Vd at steady state, intravenous administration of 3. 0 mg/kg/day] The volume of distribution of Mannitol is Mannitol administered intravenously has a volume of distribution of 34. 3 L. Adefovir dipivoxil is ≤4% over the adefovir concentration range of 0. 1 to 25 μg/mL bound to plasma proteins. No protein binding information is available for Mannitol. Adefovir dipivoxil metabolism: Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. 45% of the dose is recovered as adefovir in the urine over 24 hours at steady state following 10 mg oral doses. Adefovir is not a substrate of the cytochrome P450 enzymes. Mannitol metabolism: Mannitol is metabolized only slightly, if at all, to glycogen in the liver. Adefovir dipivoxil is eliminated via Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion. Mannitol is eliminated via Mannitol is primarily excreted unchanged in the urine. Following oral inhalation of 635 mg of mannitol in healthy volunteers, 55% of the total dose was recovered unchanged in the urine; following oral or intravenous administration of 500 mg, the corresponding values were 54 and 87%, respectively. The half-life of Adefovir dipivoxil is Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7. 48 ± 1. 65 hours. The half-life of Mannitol is Mannitol has an elimination half-life of 4. 7 hours following oral administration; the mean terminal elimination half-life is similar regardless of administration route (oral, inhalation, and intravenous. The clearance of Adefovir dipivoxil is 469 ± 99. 0 mL/min [Patients with Unimpaired renal Function receiving a 10 mg single dose]. 356 ± 85. 6 mL/min [Patients with mild renal impairement receiving a 10 mg single dose] 237 ± 118 mL/min [Patients with moderate renal impairement receiving a 10 mg single dose] 91. 7 ± 51. 3 mL/min [Patients with severe renal impairement receiving a 10 mg single dose] The clearance of Mannitol is Intravenous administration of mannitol yields a total clearance of 5. 1 L/hr and renal clearance of 4. 4 L/hr. Adefovir dipivoxil toxicity includes Renal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3–10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day. Mannitol toxicity includes Mannitol overdose may result in bronchoconstriction and should be counteracted using a short-acting bronchodilator and other symptomatic and supportive care, as necessary. Brand names of Adefovir dipivoxil include Hepsera. Brand names of Mannitol include Aridol, Bronchitol, Cystosol, Osmitrol, Sag-M. No synonyms are available for Adefovir dipivoxil. Adefovir pivoxil bis-POM PMEA No synonyms are available for Mannitol. Manitol Manna Sugar Mannit Mannite Mannitol Mannitolum Adefovir dipivoxil summary: It is Adefovir dipivoxil is a nucleotide analog used to treat chronic hepatitis B. Mannitol summary: It is Mannitol is a sugar alcohol used to test for asthma, to reduce intracranial and intraocular pressure, to measure glomerular filtration rate, and to manage pulmonary symptoms associated with cystic fibrosis. Answer: Mannitol infusions can occasionally lead to acute kidney injury. 3 Nephrotoxic agents can also lead to kidney damage. 2,1 Concomitant administration of these medications may potentiate nephrotoxic effects, but the clinical relevance of this interaction is unknown.

Adefovir dipivoxil

Drug A is Bromazepam. Drug B is Pamidronic acid. The severity of the interaction is minor. Pamidronic acid may decrease the excretion rate of Bromazepam which could result in a higher serum level. The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects. Bromazepam is indicated for the short-term treatment of insomnia, short-term treatment of anxiety or panic attacks, if a benzodiazepine is required, and the alleviation of the symptoms of alcohol- and opiate-withdrawal. Pamidronic acid is indicated for Pamidronate is indicated to treat moderate to severe hypercalcemia of malignancy, moderate to severe Paget's disease of bone, osteolytic bone metastases of breast cancer, and osteolytic lesions of multiple myeloma. Bromazepam pharmacodynamics: Bromazepam is a lipophilic, long-acting benzodiazepine and with sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties. It does not possess any antidepressant qualities. Bromazepam, like other benzodiazepines, presents a risk of abuse, misuse, and dependence. According to many psychiatric experts, Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. Pamidronic acid pharmacodynamics: Pamidronic acid is a second generation, nitrogen containing bisphosphonate that inhibits osteoclast mediated bone loss It has a wide therapeutic index and a long duration of action as it can be given every 3-4 weeks for certain indications. Patients should be counselled regarding the risk of elevated blood urea nitrogen, renal tubular necrosis, and nephrotoxicity. The mechanism of action of Bromazepam is that it Bromazepam binds to the GABA-A receptor producing a conformational change and potentiating its inhibitory effects. Other neurotransmitters are not influenced. The mechanism of action of Pamidronic acid is that it Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. Nitrogen containing bisphosphonates such as pamidronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the components of the mevalonate pathway farnesyl diphosphate synthase, farnesyl diphosphate, and geranylgeranyl diphosphate. These components are essential for post-translational prenylation of GTP-binding proteins like Rap1. The lack of prenylation of these proteins interferes with their function, and in the case of Rap1, leads to apoptosis. pamidronate also activated caspases 3 and 9 which further contribute to apoptosis. Bromazepam absorption: Bioavailability is 84% following oral administration. The time to peak plasma level is 1 - 4 hours. Bromazepam is generally well absorbed after oral administration. Pamidronic acid absorption: In patients with a creatinine clearance >90mL/min, a 90mg intravenous dose reached a Cmax of 1. 92±1. 08µg/mL, with a Tmax of 4h, and an AUC of 10. 2±6. 95µg*h/mL. In patients with a creatinine clearance 61-90mL/min, a 90mg intravenous dose reached a Cmax of 1. 86±0. 50µg/mL, with a Tmax of 4h, and an AUC of 10. 7—3. 91µg*h/mL. [A203264 In patients with a creatinine clearance 30-60mL/min, a 90mg intravenous dose reached a Cmax of 1. 84±0. 58µg/mL, with a Tmax of 4h, and an AUC of 10. 1±3. 38µg*h/mL. In patients with a creatinine clearance <30mL/min, a 90mg intravenous dose reached a Cmax of 1. 93±0. 53µg/mL, with a Tmax of 4h, and an AUC of 34. 0±8. 37µg*h/mL. The volume of distribution of Bromazepam is 1. 56 L/kg. No volume of distribution information is available for Pamidronic acid. Bromazepam is 70% bound to plasma proteins. Pamidronic acid is Pamidronate is approximately 54% protein bound in serum. bound to plasma proteins. Bromazepam metabolism: Hepatically, via oxidative pathways (via an enzyme belonging to the Cytochrome P450 family of enzymes). One of the main metabolites is 3-hydroxybromazepam. It is pharmacologically active and the half life is similar to that of the parent compound. Pamidronic acid metabolism: Pamidronate is not metabolized in vivo. Bromazepam is eliminated via Urine (69%), as metabolites. Pamidronic acid is eliminated via Pamidronate is exclusively eliminated in the urine. By 120 hours after administration, 46±16% of the dose has been eliminated in the urine. The half-life of Bromazepam is 10-20 hours. The half-life of Pamidronic acid is The mean elimination half life of pamidronate is 28±7 hours. The clearance of Bromazepam is 0. 82 mL/min/kg. The clearance of Pamidronic acid is The mean total clearance of pamidronate is 107±50mL/min and the mean renal clearance is 49±28mL/min. No toxicity information is available for Bromazepam. Pamidronic acid toxicity includes Patients experiencing and overdose may present with hypocalcemia, fever, hypotension, and taste perversion. Overdose can be managed by symptomatic and supportive treatment which may include the administration of steroids and intravenous calcium. Brand names of Bromazepam include No brand names available. Brand names of Pamidronic acid include Pamisol. No synonyms are available for Bromazepam. No synonyms are available for Pamidronic acid. Bromazepam summary: It is Bromazepam is a short-acting benzodiazepine with intermediate onset commonly used to treat panic disorders and severe anxiety. Pamidronic acid summary: It is Pamidronic acid is a bisphosphonate used to treat Paget's disease, to treat hypercalcemia of malignancy, and to treat osteolytic bone lesions. Answer: The subject drug is a nephrotoxic agent that may potentially impair renal function and decrease the excretion of drugs that mainly undergo renal excretion as the principal mode of clearance, such as the affected drug. Attenuated renal excretion of the affected drug may increase drug concentrations, leading to an elevated risk for drug-related adverse effects.

Bromazepam

Drug A is Acebutolol. Drug B is Salsalate. The severity of the interaction is moderate. Salsalate may decrease the antihypertensive activities of Acebutolol. Non-steroidal anti-inflammatory drugs (NSAIDs) can produce vasoconstriction leading to an increase in blood pressure 2,3,1. This can increase the risk of hypertension in those being treated with beta-blocker anti-hypertensives. Acebutolol is indicated for the management of hypertension and ventricular premature beats in adults. Salsalate is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorders. Acebutolol pharmacodynamics: Acebutolol is a cardioselective, beta-adrenoreceptor blocking agent, which possesses mild intrinsic sympathomimetic activity (ISA) in its therapeutically effective dose range. In general, beta-blockers reduce the work the heart has to do and allow it to beat more regularly. Acebutolol has less antagonistic effects on peripheral vascular ß2-receptors at rest and after epinephrine stimulation than nonselective beta-antagonists. Low doses of acebutolol produce less evidence of bronchoconstriction than nonselective agents like propranolol but more than atenolol. Salsalate pharmacodynamics: Salsalate is a nonsteroidal anti-inflammatory agent for oral administration. Salsalate's mode of action as an anti-inflammatory and antirheumatic agent may be due to inhibition of synthesis and release of prostaglandins. The usefulness of salicylic acid, the active in vivo product of salsalate, in the treatment of arthritic disorders has been established. In contrast to aspirin, salsalate causes no greater fecal gastrointestinal blood loss than placebo. The mechanism of action of Acebutolol is that it Acebutolol is a selective β1-receptor antagonist. Activation of β1-receptors by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Acebutolol blocks these receptors, lowering the heart rate and blood pressure. This drug then has the reverse effect of epinephrine. In addition, beta blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. The mechanism of action of Salsalate is that it The mode of anti-inflammatory action of salsalate and other nonsteroidal anti-inflammatory drugs is not fully defined, but appears to be primarily associated with inhibition of prostaglandin synthesis. This inhibition of prostaglandin synthesis is done through the inactivation of cyclooxygenase-1 (COX-1) and COX-2, which are reponsible for catalyzing the formation of prostaglandins in the arachidonic acid pathway. Although salicylic acid (the primary metabolite of salsalate) is a weak inhibitor of prostaglandin synthesis in vitro, salsalate appears to selectively inhibit prostaglandin synthesis in vivo, providing anti-inflammatory activity equivalent to aspirin and indomethacin. Unlike aspirin, salsalate does not inhibit platelet aggregation. Acebutolol absorption: Well absorbed from the Gl tract with an absolute bioavailability of approximately 40% for the parent compound. Salsalate absorption: Salsalate is insoluble in acid gastric fluids (< 0. 1 mg/ml at pH 1. 0), but readily soluble in the small intestine where it is partially hydrolyzed to two molecules of salicylic acid. A significant portion of the parent compound is absorbed unchanged. The amount of salicylic acid available from salsalate is about 15% less than from aspirin, when the two drugs are administered on a salicylic acid molar equivalent basis (3. 6 g salsalate/5 g aspirin). Food slows the absorption of all salicylates including salsalate. No volume of distribution information is available for Acebutolol. No volume of distribution information is available for Salsalate. Acebutolol is 26% bound to plasma proteins. Salsalate is Salicylate: 90-95% bound at plasma salicylate concentrations <100 mcg/mL; 70-85% bound at concentrations of 100-400 mcg/mL; 25-60% bound at concentrations >400 mcg/mL. bound to plasma proteins. Acebutolol metabolism: Subject to extensive first-pass hepatic biotransformation (primarily to diacetolol). Salsalate metabolism: Salsalate is readily soluble in the small intestine where it is partially hydrolyzed to two molecules of salicylic acid. A significant portion of the parent compound is absorbed unchanged and undergoes rapid esterase hydrolysis in the body. Acebutolol is eliminated via Elimination via renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall. Salsalate is eliminated via No route of elimination available. The half-life of Acebutolol is The plasma elimination half-life is approximately 3 to 4 hours. The half-life of its metabolite, diacetolol, is 8 to 13 hours. The half-life of Salsalate is The parent compound has an elimination half-life of about 1 hour. Salicylic acid (the active metabolite) biotransformation is saturated at anti-inflammatory doses of salsalate. Such capacity limited biotransformation results in an increase in the half-life of salicylic acid from 3. 5 to 16 or more hours. No clearance information is available for Acebutolol. No clearance information is available for Salsalate. Acebutolol toxicity includes Symptoms of overdose include extreme bradycardia, advanced atrioventricular block, intraventricular conduction defects, hypotension, severe congestive heart failure, seizures, and in susceptible patients, bronchospasm, and hypoglycemia. Salsalate toxicity includes Death has followed ingestion of 10 to 30 g of salicylates in adults, but much larger amounts have been ingested without fatal outcome. Brand names of Acebutolol include Sectral. Brand names of Salsalate include No brand names available. No synonyms are available for Acebutolol. Acebutololum Acetobutolol No synonyms are available for Salsalate. Disalicylsäure O-Salicylcylsalicylsäure o-Salicylsalicylic acid Salicylic acid bimolecular ester Salicyloxysalicylic acid Salicyloylsalicylic acid Salicylsalicylic acid Salsalate Salsalato Salsalatum Sasapyrin Sasapyrine Sasapyrinum Acebutolol summary: It is Acebutolol is a selective β1-receptor antagonist used for the management of hypertension and ventricular premature beats in adults. Salsalate summary: It is Salsalate is a nonsteroidal anti-inflammatory agent used in the symptomatic relief of rheumatoid arthritis, osteoarthritis and related rheumatic disorders. Answer: Non-steroidal anti-inflammatory drugs (NSAIDs) can produce vasoconstriction leading to an increase in blood pressure 2,3,1. This can increase the risk of hypertension in those being treated with beta-blocker anti-hypertensives.

Acebutolol

Drug A is Brentuximab vedotin. Drug B is Venetoclax. The severity of the interaction is moderate. The serum concentration of Brentuximab vedotin can be increased when it is combined with Venetoclax. MMAE (monomethyl Auristatin E), which is released after the administration of Brentuximab vedotin, and is an essential microtubule destabilizer in cancer therapy is a substrate of p-gp. The inhibition of p-gp may lead to an increase in the serum concentration and toxic effects of brentuximab vedotin due to increased exposure to MMAE. This can lead to neutropenia. Brentuximab vedotin is indicated for Brentuximab vedotin is indicated in adult patients for the treatment of previously untreated stage III or IV classical Hodgkin's lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine. It is also indicated for the treatment of cHL post-autologous hematopoietic stem cell transplantation (auto-HSCT) in patients at high risk of relapse or progression. Finally, it may be used in the treatment of adult patients with cHL who have previously failed either auto-HSCT or at least two prior multi-agent chemotherapy regimens if they are not candidates for auto-HSCT. Brentuximab vedotin is additionally indicated in the treatment of previously untreated systemic anaplastic large cell lymphoma (sALCL), or other CD30-expressing peripheral T-cell lymphomas (PTCL), in combination with cyclophosphamide, doxorubicin, and prednisone. It may also be used as monotherapy in sALCL after therapeutic failure of a least one prior multi-agent chemotherapy regimen. Brentuximab vedotin is also indicated in the treatment of primary cutaneous large anaplastic large cell lymphoma, or CD30-expressing mycosis fungoides, who have received prior systemic therapy. Venetoclax is indicated for Venetoclax is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). It is also used in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Brentuximab vedotin pharmacodynamics: Brentuximab vedotin causes apoptosis of tumor cells by preventing cell cycle progression of the G2 to M phase through disruption of the cytosolic microtuble network, thus preventing tumor growth and proliferation. Hodgkin lymphoma (HL) is characterized by malignant Reed-Sternberg cells which express CD30, a marker of large cell lymphoma. Until March 2018, USA National Comprehensive Cancer Network guidelines for patients with advanced HL (stage III/IV disease) recommend treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), or escalated bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) as first-line regimens. ABVD appears to be as effective, with fewer side effects, as escalated BEACOPP. Escalated BEACOPP leads to a greater progression-free survival but no difference in overall survival. Recent progress in technology has enabled a new shift to cancer therapy targeting specific molecules. Brentuximab vedotin, a CD30-directed antibody conjugate, selectively targets malignant HL cells. The effect of Brentuximab vedotin (1. 8 mg/kg) on the QTc interval was studied in an open-label, single-group study in 46 patients diagnosed with CD30-expressing hematologic malignancies. Ingestion of brentuximab vedotin did not prolong the mean cardiac QTc interval >10 ms from baseline levels. Smaller increases in the mean QTc interval (<10 ms) cannot be ruled out because this study did not include a placebo arm and a positive control arm. Venetoclax pharmacodynamics: Venetoclax induces rapid and potent onset apoptosis of CLL cells, powerful enough to act within 24h and to lead to tumor lysis syndrome,,. Selective targeting of BCL2 with venetoclax has demonstrated a manageable safety profile and has been shown to induce significant response in patients with relapsed CLL (chronic lymphocytic leukemia) or SLL (small lymphocytic leukemia), including patients with poor prognostic features. This drug is not expected to have a significant impact on the cardiac QT interval. Venetoclax has demonstrated efficacy in various types of lymphoid malignancies, including relapsed/ refractory CLL harboring deletion 17p, with an overall response rate of approximately 80%. The mechanism of action of Brentuximab vedotin is that it Brentuximab vedotin is composed of 3 parts: a chimeric human-murine IgG1 that selectively targets CD30, monomethyl auristatin E (MMAE), which is a microtubule-disrupting agent, and a protease-susceptible linker that links the antibody and MMAE. The IgG1 antibody enables Brentuximab vedotin to target tumor cells expressing CD30 on their surface. Following this Brentuximab vedotin enters the cell. Once inside, the linker is cleaved releasing MMAE which binds disrupts the microtubule network. The antibody component of this drug is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule-disrupting particle. MMAE is covalently attached to the antibody by a linker. Data suggest that the anticancer activity of Adcertris is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the subsequent release of MMAE by proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptotis of the malignant cells. The mechanism of action of Venetoclax is that it Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are necessary regulators of the apoptotic (anti-cell programmed death) process. This family comprises proapoptotic and prosurvival proteins for various cells. Cancer cells evade apoptosis by inhibiting programmed cell death (apoptosis). The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has demonstrated clinical efficacy in some BCL-2-dependent hematological cancers. Selective inhibition of BCL-2 by venetoclax, sparing BCL-xL enables therapeutic induction of apoptosis without the negative effect of thrombocytopenia,. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins, leading to mitochondrial outer membrane permeabilization and the activation of caspase enzymes. In nonclinical studies, venetoclax has shown cytotoxic activity in tumor cells that overexpress BCL-2. Brentuximab vedotin absorption: Steady-state of the ADC is achieved within 21 days with every 3-week dosing of Adcetris. Minimal to no accumulation of ADC is observed with multiple doses at the every 3-week schedule. The time to maximum concentration for MMAE ranges from approximately 1 to 3 days. Similar to the ADC, steady-state of MMAE is achieved within 21 days with every 3-week dosing of Adcetris. MMAE exposures decrease with continued administration of Adcetris with about 50% to 80% of the exposure of the first dose being observed at future doses. The AUC of MMAE was measured to be approximately 2. 2-fold higher in patients with hepatic impairment in comparison with patients with normal hepatic function. Venetoclax absorption: Following several oral administrations after a meal, the maximum plasma concentration of venetoclax was reached 5-8 hours after the dose. Venetoclax steady state AUC (area under the curve) increased proportionally over the dose range of 150-800 mg. After a low-fat meal, venetoclax mean (± standard deviation) steady-state Cmax was 2. 1 ± 1. 1 μg/mL and AUC0-24 was 32. 8 ± 16. 9 μg•h/mL at the 400 mg once daily dose. When compared with the fasted state, venetoclax exposure increased by 3. 4 times when ingested with a low-fat meal and 5. 2 times with a high-fat meal. When comparing low versus high fat, the Cmax and AUC were both increased by 50% when ingested with a high-fat meal. The FDA label indicataes that venetoclax should be taken with food,. The volume of distribution of Brentuximab vedotin is MMAE is unlikely to displace or to be displaced by highly protein-bound drugs. In vitro studies show that MMAE is a substrate of P-gp and was not a potent inhibitor of P-gp. The volume of distribution of Venetoclax is The population estimate for apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L. Brentuximab vedotin is In vitro, the binding of MMAE to human plasma proteins is in the range of 68–82%. bound to plasma proteins. Venetoclax is Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0. 01 across a concentration range of 1-30 µM (0. 87-26 µg/mL). The mean blood-to-plasma ratio was 0. 57. bound to plasma proteins. Brentuximab vedotin metabolism: Data in both animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes. Venetoclax metabolism: In vitro studies demonstrated that venetoclax is predominantly metabolized as a substrate of CYP3A4/5,,. Brentuximab vedotin is eliminated via This drug appears follow metabolite kinetics, with the elimination of appearing to be limited by its rate of release from the antibody-drug conjugate (ADC). An excretion study was done in patients receiving a dose of 1. 8 mg/kg of Adcetris. About 24% of the total MMAE ingested as part of the ADC during an ADCETRIS infusion was recovered in both urine and feces over a 7-day time frame. Of the recovered MMAE, approximately 72% was found in the feces and the majority of the excreted MMAE was excreted as unchanged drug. Venetoclax is eliminated via After single oral administration of 200 mg radiolabeled [14C]-venetoclax dose to healthy subjects, >99. 9% of the dose was found in feces and <0. 1% of the dose was excreted in urine within 9 days, suggesting that hepatic elimination is responsible for the clearance of venetoclax from systemic circulation. Unchanged venetoclax accounted for 20. 8% of the radioactive dose excreted in feces. The half-life of Brentuximab vedotin is The terminal half-life is approximately 4-6 days. The half-life of Venetoclax is The half-life of venetoclax is reported to be 19-26 hours, after administration of a single 50-mg dose,. The clearance of Brentuximab vedotin is The liver is the primary route of clearance for MMAE. The pharmacokinetics and safety of Brentuximab vedotin and MMAE were examined after the administration of 1. 2 mg/kg of Adcetris to patients with mild, moderate, and severe hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ≥Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function. It is recommended to avoid use in patients with severe renal impairment (CrCl <30mL/min). The clearance of Venetoclax is Mainly hepatic. Brentuximab vedotin toxicity includes The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML) follows infection by the JC virus (which is not related to Creutzfeldt-Jakob disease). Symptoms of this condition begin insidiously and usually worsen progressively. The symptoms vary depending on which region of the brain is infected. In about two out of three patients, mental function deteriorates rapidly, leading to dementia. Speaking and walking may become increasingly difficult. Vision may be impaired, and total blindness may occur. Rarely, headaches and seizures can occur, mainly in immunocompromised patients. The most serious sequela of this condition is death. Common adverse effects of Adcetris may include: neutropenia, anemia, peripheral neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and fever. In one trial, neutropenia occurred in 91 percent of patients treated with Adcetris plus chemotherapy, which was associated with a 19 percent rate of febrile neutropenia (neutropenia and fever). Preventive treatment with G-CSF, a growth factor for the bone marrow to produce white blood cells, is recommended with Adcetris plus chemotherapy for the first-line treatment of Stage III or IV cHL. Adcetris has a boxed warning that emphasizes the risk of John Cunningham virus infection leading to progressive multifocal leukoencephalopathy, or PML, a rare but serious brain infection that may be lethal. Serious risks of Adcetris include peripheral neuropathy; severe allergic (anaphylaxis) or infusion-site reactions; damage to the blood, lungs and liver (hematologic, pulmonary and hepato-toxicities); severe/opportunistic infections; metabolic abnormalities (tumor lysis syndrome); dermatologic reactions and gastrointestinal complications. Adcetris may cause harm to the fetus and newborn baby; women should be warned of the potential risk to the fetus and to use effective contraception, and to avoid breastfeeding while taking Adcetris. MMAE was found to be genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting drug. Fertility studies with Brentuximab vedotin or MMAE have not been conducted. Despite this, results of repeat-dose toxicity studies in rats suggest the potential for Brentuximab vedotin to have a negative effect on male reproductive function and fertility. In a 4-week repeated-dose toxicity study in rats with weekly dosing at 0. 5, 5 or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed. Effects in animals were seen mostly at 5 and 10 mg/kg doses of brentuximab vedotin. These dosages are approximately 3 and 6-fold the human recommended dose of 1. 8 mg/kg, respectively, based on individual body weight. Venetoclax toxicity includes Acute toxicity: oral toxicity (LD50) >2001 mg/kg (mouse). Venetoclax may cause embryo-fetal harm when administered to a pregnant woman. Patients should avoid pregnancy during treatment. A risk to human male fertility exists based on the results of testicular toxicity (germ cell loss) seen in dogs at exposures as low as 0. 5 times the human AUC exposure at the recommended dose. Carcinogenicity studies have not yet been performed with venetoclax. Venetoclax was not shown to be mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce aberrations in an in vitro chromosome aberration assay with human peripheral blood lymphocytes. It was not clastogenic in an in vivo mouse bone marrow micronucleus assay at doses up to 835 mg/kg. The M27 metabolite was negative for genotoxic activity during both in vitro Ames and chromosome aberration assays. Brand names of Brentuximab vedotin include Adcetris. Brand names of Venetoclax include Venclexta. No synonyms are available for Brentuximab vedotin. No synonyms are available for Venetoclax. 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide Brentuximab vedotin summary: It is Brentuximab vedotin is a CD30-directed antibody-drug conjugate used to treat various types of lymphoma. Venetoclax summary: It is Venetoclax is a BCL-2 inhibitor used to treat chronic lymphocytic leukemia, small lymphocytic lymphoma, or acute myeloid leukemia. Answer: MMAE (monomethyl Auristatin E), which is released after the administration of Brentuximab vedotin, and is an essential microtubule destabilizer in cancer therapy is a substrate of p-gp. The inhibition of p-gp may lead to an increase in the serum concentration and toxic effects of brentuximab vedotin due to increased exposure to MMAE. This can lead to neutropenia.

Brentuximab vedotin