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Drug A is Protein C. Drug B is Daunorubicin. The severity of the interaction is minor. The risk or severity of bleeding can be increased when Protein C is combined with Daunorubicin. 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. 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. 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. 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 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 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. Protein C absorption: Cmax = 110 IU/dL. Tmax = 0. 50 hr 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 Protein C is Volume of distribution at steady state = 0. 74 dL/kg. 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. No protein binding information is available for Protein C. No protein binding information is available for Daunorubicin. No metabolism information is available for Protein C. No metabolism information is available for Daunorubicin. Protein C is eliminated via No route of elimination available. 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 Protein C is Initial half life = 7. 8 hr. Terminal half life = 9. 9 hr 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 Protein C is CL = 0. 0533 dL/kg/h. The clearance of Daunorubicin is Daunorubicin has a clearance of 68. 4 mL/h/m determined using the liposomal formulation. No toxicity information is available for Protein C. No toxicity information is available for Daunorubicin. Brand names of Protein C include Balfaxar, Beriplex, Ceprotin, Kcentra, Octaplex. Brand names of Daunorubicin include Cerubidine, Vyxeos. No synonyms are available for Protein C. No synonyms are available for Daunorubicin. Daunomycin Daunorubicin liposomal Daunorubicina Daunorubicine Daunorubicinum Leukaemomycin C Rubidomycin 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. Daunorubicin summary: It is Daunorubicin is an anthracycline aminoglycoside used to induce remission of nonlymphocytic leukemia and acute lymphocytic leukemia. 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 Buclizine. Drug B is Sotalol. The severity of the interaction is moderate. The risk or severity of QTc prolongation can be increased when Buclizine is combined with Sotalol. The subject drug may prolong the QTc interval. The affected drug has a high 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. Buclizine is indicated for prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness and vertigo (dizziness caused by other medical problems). Sotalol is indicated for Sotalol is indicated to treat life threatening ventricular arrhytmias and maintain normal sinus rhythm in patients with atrial fibrillation or flutter. There are also oral solutions and intravenous injections indicated for patients requiring sotalol, but for whom a tablet would not be appropriate. Buclizine pharmacodynamics: Buclizine is a piperazine-derivative antihistamine used as an antivertigo/antiemetic agent. Buclizine is used in the prevention and treatment of nausea, vomiting, and dizziness associated with motion sickness. Additionally, it has been used in the management of vertigo in diseases affecting the vestibular apparatus. Although the mechanism by which buclizine exerts its antiemetic and antivertigo effects has not been fully elucidated, its central anticholinergic properties are partially responsible. The drug depresses labyrinth excitability and vestibular stimulation, and it may affect the medullary chemoreceptor trigger zone. It also possesses anticholinergic, antihistaminic, central nervous system depressant, and local anesthetic effects. Sotalol pharmacodynamics: Sotalol is a competitive inhibitor of the rapid potassium channel. This inhibition lengthens the duration of action potentials and the refractory period in the atria and ventricles. The inhibition of rapid potassium channels is increases as heart rate decreases, which is why adverse effects like torsades de points is more likely to be seen at lower heart rates. L-sotalol also has beta adrenergic receptor blocking activity seen above plasma concentrations of 800ng/L. The beta blocking ability of sotalol further prolongs action potentials. D-sotalol does not have beta blocking activity but also reduces a patient's heart rate while standing or exercising. These actions combine to produce a negative inotropic effect that reduces the strength of contractility of muscle cells in the heart. Extension of the QT interval is also adversely associated with the induction of arrhythmia in patients. Hyperglycemia is a greater risk for non insulin dependant diabetics than insulin dependant diabetics. Beta blockers inhibit insulin secretion which may cause hyperglycemia in type II diabetes mellitus. The risk of hypoglycemia is higher in insulin dependant diabetes than non insulin dependant diabetics. Beta blockers decrease secretion of insulin, which may mask hypoglycemia in an insulin dependant patient. Beta blockers also increase glucose uptake into cells which may prolong or potentiate hypoglycemia. Further information regarding adverse reactions can be found here. The mechanism of action of Buclizine is that it Vomiting (emesis) is essentially a protective mechanism for removing irritant or otherwise harmful substances from the upper GI tract. Emesis or vomiting is controlled by the vomiting centre in the medulla region of the brain, an important part of which is the chemotrigger zone (CTZ). The vomiting centre possesses neurons which are rich in muscarinic cholinergic and histamine containing synapses. These types of neurons are especially involved in transmission from the vestibular apparatus to the vomiting centre. Motion sickness principally involves overstimulation of these pathways due to various sensory stimuli. Hence the action of buclizine which acts to block the histamine receptors in the vomiting centre and thus reduce activity along these pathways. Furthermore since buclizine possesses anti-cholinergic properties as well, the muscarinic receptors are similarly blocked. The mechanism of action of Sotalol is that it Sotalol inhibits beta-1 adrenoceptors in the myocardium as well as rapid potassium channels to slow repolarization, lengthen the QT interval, and slow and shorten conduction of action potentials through the atria. The action of sotalol on beta adrenergic receptors lengthens the sinus node cycle, conduction time through the atrioventricular node, refractory period, and duration of action potentials. Buclizine absorption: Rapidly absorbed following oral administration. Sotalol absorption: Sotalol is 90-100% bioavailable. When taken with a meal, adsorption is lowered by 18%. In patients with a creatinine clearance >80mL/min, the maximum concentration is 6. 25±2. 19. No volume of distribution information is available for Buclizine. The volume of distribution of Sotalol is The apparent volume of distribution is 1. 2-2. 4L/kg. No protein binding information is available for Buclizine. Sotalol is 0%. bound to plasma proteins. Buclizine metabolism: Hepatic. Sotalol metabolism: Sotalol is not metabolized. Buclizine is eliminated via No route of elimination available. Sotalol is eliminated via 80-90% of a given dose is excreted in the urine as unchanged sotalol. A small fraction of the doses is excreted in the feces as unchanged sotalol. The half-life of Buclizine is No half-life available. The half-life of Sotalol is The terminal elimination half life is 10-20 hours in healthy patients. In patients with a creatinine clearance >80mL/min, the half life is 17. 5±0. 97h. In patients with a creatinine clearance 30-80mL/min, the half life is 22. 7±6. 4h. In patients with a creatinine clearance 10-30mL/min, the half life is 64±27. 2h. In patients with a creatinine clearance <10mL/min, the half life is 97. 9±57. 3h. No clearance information is available for Buclizine. The clearance of Sotalol is In patients with a creatinine clearance >80mL/min, the plasma clearance is 6. 78±2. 72L/h and the renal clearance is 4. 99±1. 43L/h. In patients with a creatinine clearance 30-80mL/min, the plasma clearance is 2. 74±0. 53L/h and the renal clearance is 2. 00±0. 67L/h. In patients with a creatinine clearance 10-30mL/min, the plasma clearance is 1. 56±0. 44L/h and the renal clearance is 0. 65±0. 31L/h. In patients with a creatinine clearance <10mL/min, the plasma clearance is 0. 65±0. 20L/h and the renal clearance is 0. 27±0. 13L/h. No toxicity information is available for Buclizine. Sotalol toxicity includes Patients experiencing an overdose may present with bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. Larger intentional overdoses may present as hypotension, bradycardia, cardiac asystole, prolonged QT interval, torsade de pointes, ventricular tachycardia, and premature ventricular complexes. Stop administering sotalol and observe the patient until the QT interval returns to normal and the heart rate rises above 50 beats per minute. Hemodialysis may help lower plasma concentrations of sotalol as it is not bound to plasma proteins. Bradycardia and cardiac asystole may be treated with atropine, other anticholinergic drugs, beta adrenergic agonists, or transvenous cardiac pacing. Second or third degree heart block may be treated with a transvenous cardiac pacemaker. Hypotension may be treated with epinephrine or norepinephrine. Bronchospasm may be treated with aminophylline or a beta-2 agonist, possibly at higher than normal doses. Torsade de pointes may be treated with DC cardioversion, transvenous cardiac pacing, epinephrine, or magnesium sulfate. The oral LD50 for rats is 3450mg/kg, intraperitoneal LD50 for rats is 680mg/kg, oral LD50 for mice is 2600mg/kg, and intraperitoneal LD50 for mice is 670mg/kg. Pregnant rabbits given 6 times the maximum recommended human dose showed an increase in fetal death and maternal toxicity, while rats given 18 times the maximum recommended human dose had an increased number of fetal resorptions. Sotalol is present in human breast milk so patients taking sotalol should not breast feed. Sotalol has not been found to be carcinogenic. No studies have been performed regarding mutagenicity or clastogenicity. In animal studies, sotalol was not associated with a reduction in fertility aside from smaller litter sizes. Further information regarding adverse reactions can be found here. Brand names of Buclizine include No brand names available. Brand names of Sotalol include Betapace, Sorine, Sotylize. No synonyms are available for Buclizine. Buclizine Buclizinum No synonyms are available for Sotalol. Sotalolo Sotalolum Buclizine summary: It is Buclizine is an antihistamine and antiemetic drug for the treatment of allergy symptoms and prevention of nausea and vomiting. Sotalol summary: It is Sotalol is a methane sulfonanilide beta adrenergic antagonist used to treat life-threatening ventricular arrhythmias and to maintain sinus rhythm in atrial fibrillation or flutter. Answer: The subject drug may prolong the QTc interval. The affected drug has a high 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.

Buclizine

Drug A is Obinutuzumab. Drug B is Estramustine. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Estramustine is combined with Obinutuzumab. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Obinutuzumab is indicated for Obinutuzumab is used as a combination treatment with chlorambucil to treat patients with untreated chronic lymphocytic leukemia. Estramustine is indicated for the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Obinutuzumab pharmacodynamics: Obinutuzumab is more potent than rituximab in depleting B-cells, antitumor activity, and tumor regression. Estramustine pharmacodynamics: Estramustine is an antineoplastic agent indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a combination of estradiol with nitrogen mustard. In vivo, the nitrogen-mustard moiety becomes active and participates in alkylation of DNA or other cellular components. This causes DNA damage in rapidly dividing cancerous cells leading to cell death and ideally, tumor shrinkage. 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 Estramustine is that it Estramustine is a derivative of estradiol with a nitrogen mustard moiety. This gives it alkylating properties. In vivo, the nitrogen mustard component is active and can alklyate DNA and other cellular components (such as tubulin components) of rapidly dividing cells. This causes DNA strandbreaks or misscoding events. This leads to apoptosis and cell death. Also, due to the drugs estrogen component, it can bind more selectively to active estrogen receptors. Obinutuzumab absorption: Obinutuzumab is administered intravenously, so its absorption is 100%. No absorption information is available for Estramustine. The volume of distribution of Obinutuzumab is Obinutuzumab has a volume of distribution of about 3. 8 L. No volume of distribution information is available for Estramustine. Obinutuzumab is Obinutuzumab does not bind to plasma proteins. bound to plasma proteins. No protein binding information is available for Estramustine. Obinutuzumab metabolism: Obinutuzumab is not metabolized by the liver. No metabolism information is available for Estramustine. Obinutuzumab is eliminated via The route of elimination of obinutuzumab was not indicated (FDA label). Estramustine is eliminated via The metabolic urinary patterns of the estradiol moiety of estramustine phosphate and estradiol itself are very similar, although the metabolites derived from estramustine phosphate are excreted at a slower rate. The half-life of Obinutuzumab is The half life of obinutuzumab is 28. 4 days. The half-life of Estramustine is 20 hours. The clearance of Obinutuzumab is The clearance of obinutuzumab is 0. 09L/day. No clearance information is available for Estramustine. 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. No toxicity information is available for Estramustine. Brand names of Obinutuzumab include Gazyva. Brand names of Estramustine include Emcyt. No synonyms are available for Obinutuzumab. No synonyms are available for Estramustine. Estramustine Estramustinum Obinutuzumab summary: It is Obinutuzumab is an antineoplastic CD20 antibody used to treat untreated chronic lymphocytic leukemia in combination with chlorambucil. Estramustine summary: It is Estramustine is an antineoplastic agent used for the management of metastatic and/or progressive prostate cancer in palliative setting. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Obinutuzumab

Drug A is Oxytocin. Drug B is Vorinostat. The severity of the interaction is minor. The risk or severity of QTc prolongation can be increased when Oxytocin 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. 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. 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. 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. Vorinostat pharmacodynamics: No pharmacodynamics available. 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 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. 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 Vorinostat. No volume of distribution information is available for Oxytocin. No volume of distribution information is available for Vorinostat. No protein binding information is available for Oxytocin. Vorinostat is 71% 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. 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). 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. 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 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 Vorinostat is 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 Vorinostat. 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 Vorinostat. Brand names of Oxytocin include Pitocin. Brand names of Vorinostat include Zolinza. No synonyms are available for Oxytocin. No synonyms are available for Vorinostat. SAHA Suberanilohydroxamic acid Suberoylanilide hydroxamic acid Vorinostat Vorinostatum 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. 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.

Oxytocin

Drug A is Asparaginase Erwinia chrysanthemi. Drug B is Carbamazepine. The severity of the interaction is moderate. The therapeutic efficacy of Carbamazepine can be increased when used in combination with Asparaginase Erwinia chrysanthemi. The subject drug is known to significantly decrease the level of thyroxine-binding globulin which is one of the main carriers for the affected drug. Hence, the concomitant administration of these drugs will produce a decrease in the protein binding of the affected drug which may increase its therapeutic effect. Asparaginase Erwinia chrysanthemi is indicated for Asparaginase Erwinia chrysanthemi is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma in adults and children who have developed hypersensitivity to E. coli -derived asparaginase. Carbamazepine is indicated for Carbamazepine is indicated for the treatment of epilepsy and pain associated with true trigeminal neuralgia. In particular, carbamazepine has shown efficacy in treating mixed seizures, partial seizures with complex symptoms, and generalized tonic-clonic seizures. Carbamazepine is also indicated for the treatment of manic episodes and mixed manic-depressive episodes caused by bipolar I disorder. Some off-label, unapproved uses of carbamazepine include the treatment of alcohol withdrawal syndrome and restless leg syndrome. Asparaginase Erwinia chrysanthemi pharmacodynamics: Asparaginase Erwinia chrysanthemi is an enzyme that exerts cytotoxic effects on leukemic cells by depleting the source of an amino acid asparagine, which plays a role in the proliferation, protein metabolism, and survival of malignant cells. Carbamazepine pharmacodynamics: General effects Carbamazepine treats seizures and the symptoms of trigeminal neuralgia by inhibiting sodium channels. In bipolar 1 disorder, carbamazepine has been found to decrease mania symptoms in a clinically significant manner according to the Young Mania Rating Scale (YMRS). Carbamazepine has a narrow therapeutic index. A note on genetic variation and carbamazepine use In studies of Han Chinese ancestry patients, a pronounced association between the HLA-B*1502 genotype and Steven Johnson syndrome and/or toxic epidermal necrolysis (SJS/TEN) resulting from carbamazepine use was observed. The mechanism of action of Asparaginase Erwinia chrysanthemi is that it Asparaginase Erwinia chrysanthemi is a tetrameric enzyme made up of four identical subunits, each having a molecular weight of about 35 kDa. It rapidly and completely catalyzes the deamidation reaction of L-asparagine to aspartic acid and ammonia, resulting in reduced levels of circulating asparagine in the plasma. Asparagine is essential for DNA synthesis, RNA synthesis, protein metabolism, and survival of leukemic cells; however, they lack the asparagine synthetase enzyme and depend on an exogenous source of asparagine. Asparaginase Erwinia chrysanthemi depletes the source of asparagine for leukemic cells, resulting in the death of leukemic cells. In addition to asparagine, asparaginase Erwinia chrysanthemi also deaminates glutamine to a lesser extent. The mechanism of action of Carbamazepine is that it Carbamazepine's mechanism of action is not fully elucidated and is widely debated. One major hypothesis is that carbamazepine inhibits sodium channel firing, treating seizure activity. Animal research studies have demonstrated that carbamazepine exerts its effects by lowering polysynaptic nerve response and inhibiting post-tetanic potentiation. In both cats and rats, carbamazepine was shown to decrease pain caused by infraorbital nerve stimulation. A decrease in the action potential in the nucleus ventralis of the thalamus in the brain and inhibition of the lingual mandibular reflex were observed in other studies after carbamazepine use. Carbamazepine causes the above effects by binding to voltage-dependent sodium channels and preventing action potentials, which normally lead to stimulatory effects on nerves. In bipolar disorder, carbamazepine is thought to increase dopamine turnover and increase GABA transmission, treating manic and depressive symptoms. A common issue that has arisen is resistance to this drug in up to 30% of epileptic patients, which may occur to altered metabolism in patients with variant genotypes. A potential therapeutic target to combat carbamazepine resistance has recently been identified as the EPHX1 gene promoter, potentially conferring resistance to carbamazepine through methylation. Asparaginase Erwinia chrysanthemi absorption: In patients two to 80 years of age, intramuscular administration of asparaginase Erwinia chrysanthemi 25,000 International Units (IU)/m resulted in serum trough asparaginase concentrations ≥ 0. 1 IU/mL at either 48-hour (n=35) or 72-hour (n=13) post third dose. 80% of patients evaluted at 48 hours and 38% of patients evaluated at 72 hours had serum asparaginase activity levels > 0. 4 IU/mL. For asparaginase Erwinia chrysanthemi (recombinant)-rywn, the median t max is 10 hours and the mean absolute bioavailability is 37% in healthy subjects. Carbamazepine absorption: The bioavailability of carbamazepine is in the range of 75-85% of an ingested dose. After one 200 mg oral extended-release dose of carbamazepine in a pharmacokinetic study, the Cmax carbamazepine was measured to be 1. 9 ± 0. 3 mcg/mL. The Tmax was 19 ± 7 hours. After several doses of 800 mg every 12 hours, the peak concentrations of carbamazepine were measured to be 11. 0 ± 2. 5 mcg/mL. The Tmax was reduced to 5. 9 ± 1. 8 hours. Extended-release carbamazepine demonstrated linear pharmacokinetics over a range of 200–800 mg. Effect of food on absorption A meal containing high-fat content increased the rate of absorption of one 400 mg dose but not the AUC of carbamazepine. The elimination half-life remained unchanged between fed and fasting state. The pharmacokinetics of an extended-release carbamazepine dose was demonstrated to be similar when administered in the fasted state or with food. Based on these findings, food intake is unlikely to exert significant effects on carbamazepine absorption. The volume of distribution of Asparaginase Erwinia chrysanthemi is The volume of distribution of asparaginase Erwinia chrysanthemi can be up to 5 L/m. The geometric mean (%CV) apparent volume of distribution of asparaginase Erwinia chrysanthemi (recombinant)-rywn was 1. 48 L/m (49%). While asparaginases are not detectable in cerebrospinal fluid, asparagine in cerebrospinal fluid is depleted with systemic administration of any formulation of asparaginases. The volume of distribution of Carbamazepine is The volume of distribution of carbamazepine was found to be 1. 0 L/kg in one pharmacokinetic study. Another study indicates that the volume of distribution of carbamazepine ranges between 0. 7 to 1. 4 L/kg. Carbamazepine crosses the placenta, and higher concentrations of this drug are found in the liver and kidney as opposed to lung and brain tissue. Carbamazepine crosses variably through the blood-brain barrier. Asparaginase Erwinia chrysanthemi is There is limited information on protein binding. bound to plasma proteins. Carbamazepine is Carbamazepine is 75%-80% bound to plasma proteins. One pharmacokinetic study indicates that it is 72% bound to plasma proteins. bound to plasma proteins. Asparaginase Erwinia chrysanthemi metabolism: Metabolism of asparaginase Erwinia chrysanthemi has not been fully characterized; however, it is suspected to be metabolized into small peptides by catabolic pathways. Carbamazepine metabolism: Carbamazepine is largely metabolized in the liver. CYP3A4 hepatic enzyme is the major enzyme that metabolizes carbamazepine to its active metabolite, carbamazepine-10,11-epoxide, which is further metabolized to its trans-diol form by the enzyme epoxide hydrolase. Other hepatic cytochrome enzymes that contribute to the metabolism of carbamazepine are CYP2C8, CYP3A5, and CYP2B6. Carbamazepine also undergoes hepatic glucuronidation by UGT2B7 enzyme and several other metabolic reactions occur, resulting in the formation of minor hydroxy metabolites and quinone metabolites. Interestingly, carbamazepine induces its own metabolism. This leads to enhanced clearance, reduced half-life, and a reduction in serum levels of carbamazepine. Asparaginase Erwinia chrysanthemi is eliminated via Trace amounts of asparaginases are found in urine. Carbamazepine is eliminated via After an oral dose of radiolabeled carbamazepine, 72% of the administered radioactive dose was detected in the urine and the remainder of the ingested dose was found in the feces. Carbamazepine is mainly excreted as hydroxylated and conjugated metabolites, and minimal amounts of unchanged drug. The half-life of Asparaginase Erwinia chrysanthemi is The apparent half-life (%CV) of asparaginase Erwinia chrysanthemi (recombinant)-rywn is 18. 2 hours (16%). Asparaginase Erwinia chrysanthemi has a shorter half-life compared with the E. coli-derived preparations. The half-life of Carbamazepine is The mean elimination half-life of carbamazepine was 35 to 40 hours after one dose of carbamazepine extended-release formulations. The half-life ranged from 12-17 hours after several doses of carbamazepine. One pharmacokinetic study determined the elimination half-life of carbamazepine to range between 27 to 36. 8 hours in healthy volunteers. The clearance of Asparaginase Erwinia chrysanthemi is The geometric mean (%CV) apparent clearance of asparaginase Erwinia chrysanthemi (recombinant)-rywn is 0. 31 L/hour/m (36%). The clearance of Carbamazepine is In a pharmacokinetic study, the apparent oral clearance of carbamazepine was 25 ± 5 mL/min after one dose of carbamazepine and 80 ± 30 mL/min after several doses. Asparaginase Erwinia chrysanthemi toxicity includes There are no known cases of overdose with asparaginase Erwinia chrysanthemi. In clinical trials, the most common adverse effects were hypersensitivity reactions, pancreatic toxicity, blood clots, hemorrhage, and liver toxicity. Pancreatitis occurs in 8-14% of pediatric patients, with adolescents at the highest risk for developing this adverse event. Pancreatitis typically occurs after the first few weeks of asparaginase administration, which suggests this complication occurs from an underlying predisposition rather than a cumulative drug effect. Carbamazepine toxicity includes Toxicity information. Oral LDLO (female) is 1920 mg/kg/17W (intermittent); Oral LDLO (male): 54 mg/kg/9D (intermittent) Oral LD50 (rat): 1957 mg/kg Overdose information The initial signs of carbamazepine overdose occur 1-3 hours post ingestion. These signs and symptoms may vary in case of an overdose between carbamazepine and other drugs. Carbamazepine may cause various cardiovascular, neurological, respiratory, urinary symptoms as well as laboratory abnormalities including leukocytosis, reduced leucocytes, acetonuria, and glycosuria. Neuromuscular symptoms may occur initially, followed by mild cardiac symptoms such as tachycardia, hypertension, or hypotension. Higher doses of carbamazepine may cause more severed cardiovascular effects. Restlessness, muscular twitching, tremor, dilated pupils, nystagmus, psychomotor disturbances, and other neurological symptoms may occur. Hyperreflexia in the initial stages of overdose may be followed by hyporeflexia. Nausea, vomiting, urinary retention, dizziness or drowsiness may also occur. In cases of overdose, contact the local poison control center. Ensure to provide supportive and symptomatic treatment, which may include monitoring and careful supervision by a medical professional. The possibility of overdose with multiple drugs must be considered in the case of carbamazepine overdose. Maintain an adequate airway, oxygen, in addition to ventilation. Vital signs should be monitored. Brand names of Asparaginase Erwinia chrysanthemi include Erwinaze, Rylaze. Brand names of Carbamazepine include Carbatrol, Carnexiv, Epitol, Equetro, Tegretol. No synonyms are available for Asparaginase Erwinia chrysanthemi. No synonyms are available for Carbamazepine. Carbamazepin Carbamazepina Carbamazépine Carbamazepine Carbamazepinum Molecusol-Carbamazepine Asparaginase Erwinia chrysanthemi summary: It is Asparaginase Erwinia chrysanthemi is an asparagine-specific enzyme used as part of a chemotherapeutic regimen to treat patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. Carbamazepine summary: It is Carbamazepine is an anticonvulsant used to treat various types of seizures and pain resulting from trigeminal neuralgia. Answer: The subject drug is known to significantly decrease the level of thyroxine-binding globulin which is one of the main carriers for the affected drug. Hence, the concomitant administration of these drugs will produce a decrease in the protein binding of the affected drug which may increase its therapeutic effect.

Asparaginase Erwinia chrysanthemi

Drug A is Certolizumab pegol. Drug B is Edrophonium. The severity of the interaction is minor. Edrophonium 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. Edrophonium is indicated for the differential diagnosis of myasthenia gravis and as an adjunct in the evaluation of treatment requirements in this disease. It may also be used for evaluating emergency treatment in myasthenic crises. 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. Edrophonium pharmacodynamics: Edrophonium is a short and rapid-acting anticholinesterase drug. Its effect is manifest within 30 to 60 seconds after injection and lasts an average of 10 minutes. Edrophonium's pharmacologic action is due primarily to the inhibition or inactivation of acetylcholinesterase at sites of cholinergic transmission. Nicotinic acetylcholine (nAChR)receptors are found throughout the body, especially on muscle. Stimulation of these receptors causes to muscle contraction. In myasthenia gravis the body's immune system destroys many of the nicotinic acetylcholine receptors, so that the muscle becomes less responsive to nervous stimulation. Edrophonium chloride increases the amount of acetylcholine at the nerve endings. Increased levels of acetylcholine allow the remaining receptors to function more efficiently. 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 Edrophonium is that it Edrophonium works by prolonging the action acetylcholine, which is found naturally in the body. It does this by inhibiting the action of the enzyme acetylcholinesterase. Acetylcholine stimulates nicotinic and muscarinic receptors. When stimulated, these receptors have a range of effects. 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. Edrophonium absorption: Rapidly absorbed. 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 Edrophonium is 1. 6±0. 4 L/kg [Adults]. 2. 2±1. 5 L/kg [Children (0. 08-10 yrs)] 1. 8±1. 2 L/kg [Elderly (65-75 yrs)] Certolizumab pegol is Monoclonal antibodies are usually not required to have protein binding studies. bound to plasma proteins. No protein binding information is available for Edrophonium. 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. No metabolism information is available for Edrophonium. 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. Edrophonium is eliminated via Edrophonium is primarily renally excreted with 67% of the dose appearing in the urine. Hepatic metabolism and biliary excretion have also been demonstrated in animals The half-life of Certolizumab pegol is The circulatory half-life of certolizumab is of 14 days. The half-life of Edrophonium is Distribution half-life is 7 to 12 minutes. Elimination half-life is 33 to 110 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 Edrophonium is 6. 8 +/- 2. mL/kg/min [Adults]. 6. 4 +/- 3. 9 mL/kg/min [Children (0. 08-10 yrs)] 2. 9 +/- 1. 9 mL/kg/min [Elderly (65-75 yrs)] 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. Edrophonium toxicity includes With drugs of this type, muscarine-like symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions and bradycardia) often appear with overdosage (cholinergic crisis). Brand names of Certolizumab pegol include Cimzia. Brand names of Edrophonium include Enlon, Enlon-plus. No synonyms are available for Certolizumab pegol. No synonyms are available for Edrophonium. 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. Edrophonium summary: It is Edrophonium is a cholinesterase inhibitor used to diagnose and evaluate myasthenia gravis. 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 Floxuridine. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Floxuridine 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. Floxuridine is indicated for palliative management of gastrointestinal adenocarcinoma metastatic to the liver, when given by continuous regional intra-arterial infusion in carefully selected patients who are considered incurable by surgery or other means. Also for the palliative management of liver cancer (usually administered by hepatic intra-arterial infusion). 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. Floxuridine pharmacodynamics: Floxuridine is an anti-metabolite or a pyrimidine analog that works by disrupting the process S-phase of cell division, selectively targeting rapidly dividing cells. Due to the structural similarities, antimetabolites act as pyrimidine-like molecules and prevent normal pyrimidines from being incorporated into DNA. After successful biotransformation, floxuridine is converted into an active component, flurouracil, which blocks the enzyme which converts cytosine nucleosides into the deoxy derivative. Flurouracil also physically prevents the incorporation of thymidine nucleotides into the DNA strand by taking their place, further preventing DNA synthesis. 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 Floxuridine is that it Floxuridine rapidly undergoes catabolism to form 5-fluorouracil, which is the active component of the drug. 5-Fluorouracil primarily works by interfering with DNA synthesis; however, it may also inhibit the formation of fraudulent RNA via physical incorporation into the RNA. It is also an inhibitor of riboside phophorylase, preventing the utilization of pre-formed uracil in RNA synthesis. Floxuridine can also form 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP), which is the monophosphate of floxuridine that inhibits thymidylate synthetase that plays a role in the methylation of deoxyuridylic acid to thymidylic acid during DNA synthesis. FUDR-MP thus interferes with DNA synthesis. 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. No absorption information is available for Floxuridine. 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. No volume of distribution information is available for Floxuridine. Risankizumab is No information is available. bound to plasma proteins. No protein binding information is available for Floxuridine. 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. Floxuridine metabolism: Hepatic. 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. Floxuridine is eliminated via Floxuridine can be excreted as unchanged drug, urea, fluorouracil, a-fluoro-bureidopropionic acid, dihydrofluorouracil, a-fluoro-b-guanidopropionic acid and a-fluoro-b-alanine via the kidneys. Floxuridine may also be excreted as respiratory carbon dioxide. 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 Floxuridine is No half-life available. 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. No clearance information is available for Floxuridine. 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. Floxuridine toxicity includes Oral, rat LD 50: 215 mg/kg. Signs of overdose include nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, and bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis). Brand names of Risankizumab include Skyrizi 150 Mg Dose Pack. Brand names of Floxuridine include No brand names available. No synonyms are available for Risankizumab. No synonyms are available for Floxuridine. 5FDU Deoxyfluorouridine Floxiridina Floxuridin Floxuridine Floxuridinum Fluorodeoxyuridine Fluoruridine deoxyribose Risankizumab summary: It is Risankizumab is an interleukin-23 antagonist used to treat plaque psoriasis, psoriatic arthritis, and Crohn's disease in adults. Floxuridine summary: It is Floxuridine is an antimetabolite used as palliative management for liver metastases of gastrointestinal malignancy. 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 Acetylcholine. Drug B is Guanidine. The severity of the interaction is moderate. The risk or severity of adverse effects can be increased when Guanidine is combined with Acetylcholine. Due to a reduction in drug transport, OCT1 inhibitors may increase the concentration of drugs that are substrates of this transporter, leading to OCT1 substrate intolerance. Acetylcholine is indicated for Used to obtain miosis of the iris in seconds after delivery of the lens in cataract surgery, in penetrating keratoplasty, iridectomy and other anterior segment surgery where rapid miosis may be required. Guanidine is indicated for the reduction of the symptoms of muscle weakness and easy fatigability associated with the myasthenic syndrome of Eaton-Lambert. It is not indicated for treating myasthenia gravis. Acetylcholine pharmacodynamics: No pharmacodynamics available. Guanidine pharmacodynamics: Guanidine apparently acts by enhancing the release of acetylcholine following a nerve impulse. It also appears to slow the rates of depolarization and repolarization of muscle cell membranes. The mechanism of action of Acetylcholine is that it No mechanism of action available. The mechanism of action of Guanidine is that it No mechanism of action available. No absorption information is available for Acetylcholine. Guanidine absorption: Rapidly absorbed and distributed. No volume of distribution information is available for Acetylcholine. No volume of distribution information is available for Guanidine. No protein binding information is available for Acetylcholine. No protein binding information is available for Guanidine. No metabolism information is available for Acetylcholine. Guanidine metabolism: Not metabolized. Acetylcholine is eliminated via No route of elimination available. Guanidine is eliminated via No route of elimination available. The half-life of Acetylcholine is No half-life available. The half-life of Guanidine is 7-8 hours. No clearance information is available for Acetylcholine. No clearance information is available for Guanidine. No toxicity information is available for Acetylcholine. Guanidine toxicity includes LD 50 = 475 mg/kg (oral, rat). Can cause severe gastrointestinal symptoms (nausea, vomiting and diarrhea), bone marrow suppression, renal insufficiency and other hematologic abnormalities (anemia, leucopenia). Severe guanidine intoxication is characterized by nervous hyperirritability, fibrillary tremors and convulsive contractions of muscle, salivation, vomiting, diarrhea, hypoglycemia, and circulatory disturbances. Brand names of Acetylcholine include Miochol. Brand names of Guanidine include No brand names available. No synonyms are available for Acetylcholine. Choline acetate O-Acetylcholine No synonyms are available for Guanidine. Guanidin Guanidine Imidourea Iminourea Acetylcholine summary: It is Acetylcholine is a parasympathomimetic neurotransmitter used to induce miosis of the iris in seconds after delivery of the lens in cataract surgery, in penetrating keratoplasty, iridectomy and other anterior segment surgery where rapid miosis may be required. Guanidine summary: It is Guanidine is a strong organic base used to treat muscle weakness and fatigue associated with the myasthenic complications of Eaton-Lambert syndrome. Answer: Due to a reduction in drug transport, OCT1 inhibitors may increase the concentration of drugs that are substrates of this transporter, leading to OCT1 substrate intolerance.

Acetylcholine

Drug A is Belantamab mafodotin. Drug B is Sildenafil. The severity of the interaction is moderate. The serum concentration of Belantamab mafodotin can be increased when it is combined with Sildenafil. This interaction may lead to increased exposure to drugs which are p-glycoprotein substrates, increasing their risk of toxicity. Central nervous system depression, undertreated HIV infection, cardiac conduction defects, and transplant rejection are all possible outcomes if these interactions occur. 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. Sildenafil is indicated for Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor that is predominantly employed for two primary indications: (1) the treatment of erectile dysfunction; and (2) treatment of pulmonary hypertension, where:. a) the US FDA specifically indicates sildenafil for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil was added to background epoprostenol therapy. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%); b) the Canadian product monograph specifically indicates sildenafil for the treatment of primary pulmonary arterial hypertension (PPH) or pulmonary hypertension secondary to connective tissue disease (CTD) in adult patients with WHO functional class II or III who have not responded to conventional therapy. In addition, improvement in exercise ability and delay in clinical worsening was demonstrated in adult patients who were already stabilized on background epoprostenol therapy; and c) the EMA product information specifically indicates sildenafil for the treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease. The EMA label also indicates sildenafil for the treatment of pediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary hemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease. 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. Sildenafil pharmacodynamics: In vitro studies have shown that sildenafil is selective for phosphodiesterase-5 (PDE5). Its effect is more potent on PDE5 than on other known phosphodiesterases. In particular, there is a 10-times selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-times selectivity over PDE1, and over 700-times over PDE 2, 3, 4, 7, 8, 9, 10 and 11. And finally, sildenafil has greater than 4,000-times selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (via the use of RigiScan®), after sildenafil administration compared with placebo. Most studies assessed the efficacy of sildenafil approximately 60 minutes post-dose. The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. After chronic dosing of 80 mg, three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9. 4 mmHg and 9. 1 mmHg respectively. After chronic dosing of 80 mg, three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported either. In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries. Mild and transient differences in color discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (which included visual acuity, Amsler grid, color discrimination simulated traffic light, and the Humphrey perimeter and photostress test). 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 Sildenafil is that it Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i. e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. The physiological mechanism responsible for the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects. Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. 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. Sildenafil absorption: Sildenafil is known to be quickly absorbed, with maximum plasma concentrations being observed within 30-120 minutes (with a median of 60 minutes) of oral administration in a fasting patient. Moreover, the mean absolute bioavailability observed for sildenafil is about 41% (from a range of 25-63%). In particular, after oral three times a day dosing of sildenafil, the AUC and Cmax increase in proportion with dose over the recommended dosage range of 25-100 mg. When used in pulmonary arterial hypertension patients, however, the oral bioavailability of sildenafil after a dosing regimen of 80 mg three times a day, was on average 43% greater than compared to the lower doses. Finally, if sildenafil is administered orally with food, the rate of absorption is observed to be decreased with a mean delay in Tmax of about 60 minutes and a mean decrease in Cmax of approximately 29%. Regardless, the extent of absorption is not observed to be significantly affected as the recorded AUC decreased by only about 11 %. 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 Sildenafil is The mean steady-state volume of distribution documented for sildenafil is approximately 105 L - a value which suggests the medication undergoes distribution into the tissues. Belantamab mafodotin is Monoclonal antibodies are generally not protein bound. bound to plasma proteins. Sildenafil is It is generally observed that sildenafil and its main circulating N-desmethyl metabolite are both estimated to be about 96% bound to plasma proteins. Nevertheless, it has been determined that protein binding for sildenafil is independent of total drug concentrations. 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. Sildenafil metabolism: The metabolism of sildenafil is facilitated primarily by the CYP3A4 hepatic microsomal isoenzymes and to a minor extent, via the CYP2C9 hepatic isoenzymes. The predominant circulating metabolite results from the N-demethylation of sildenafil. This particular resultant metabolite possesses a phosphodiesterase selectivity that is similar to the parent sildenafil molecule and a corresponding in vitro potency for PDE5 that is approximately 50% that of the parent drug. Moreover, plasma concentrations of the metabolite are about 40% of those recorded for sildenafil, a percentage that accounts for about 20% of sildenafil’s pharmacologic effects. This primary N-desmethyl metabolite of sildenafil also undergoes further metabolism, with a terminal half-life of about 4 hours. In patients with pulmonary arterial hypertension, plasma concentrations of the primary N-desmethyl metabolite are about 72% those of the original parent sildenafil molecule after a regimen of 20 mg three times a day - which is consequently responsible for about a 36% contribution to sildenafil’s overall pharmacological effects. 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. Sildenafil is eliminated via After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). 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 Sildenafil is The terminal phase half-life observed for sildenafil is approximately 3 to 5 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. The clearance of Sildenafil is The total body clearance documented for sildenafil is 41 L/h. Belantamab mafodotin toxicity includes Data regarding overdose is not readily available. However, keratopathy was seen in 71% of patients. Sildenafil toxicity includes In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reaction (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased. Due to the lack of data on the effect of sildenafil indicated for the treatment of pulmonary arterial hypertension (PAH) in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures. The safety and efficacy of sildenafil indicated for treating PAH in a woman during labor and delivery have not been studied. Caution should ultimately be exercised when sildenafil is administered to nursing women as it is not known if sildenafil or its metabolites are excreted in human breast milk. The safety and efficacy of sildenafil for the treatment of PAH in children below 1 year of age has not been established as no data is available. Clinical experience with the elderly population in the use of sildenafil for the treatment of PAH has been varied. Some reports suggest that there are no identified differences in responses between elderly and younger patients while others have documented that clinical efficacy as measured by 6-minute walk distance could be less in elderly patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Conversely, when sildenafil was used to treat erectile dysfunction in healthy elderly volunteers (65 years or over), a reduced clearance of sildenafil was observed. This reduction resulted in about 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%. Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29- and 42- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0. 6 times the MRHD on a mg/m2 basis. Sildenafil was negative in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC. Brand names of Belantamab mafodotin include BLENREP. Brand names of Sildenafil include Liqrev, Revatio, Viagra, Vizarsin. No synonyms are available for Belantamab mafodotin. No synonyms are available for Sildenafil. Sildenafilo 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. Sildenafil summary: It is Sildenafil is a phosphodiesterase inhibitor used for the treatment of erectile dysfunction. Answer: This interaction may lead to increased exposure to drugs which are p-glycoprotein substrates, increasing their risk of toxicity. Central nervous system depression, undertreated HIV infection, cardiac conduction defects, and transplant rejection are all possible outcomes if these interactions occur.

Belantamab mafodotin

Drug A is Acenocoumarol. Drug B is Micafungin. The severity of the interaction is moderate. The therapeutic efficacy of Acenocoumarol can be increased when used in combination with Micafungin. There have been reports of changes in INR with concomitant use of antfungal agents and vitamin K antagonists although no consistent clinical effects have been established. This may be due to reduced metabolism through a cytochrome P450-mediated pharmacokinetic interaction or through effects on production of vitamin K by gut flora. 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. Micafungin is indicated for Indicated for the treatment of candidemia, acute disseminated candidiasis, and certain other invasive Candida infections, as well as esophageal candidiasis, and prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. Micafungin is also used as an alternative for the treatment of oropharyngeal candidiases and has been used with some success as primary or salvage therapy, alone or in combination with other antifungals, for the treatment of invasive aspergillosis. Indicated for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. 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. Micafungin pharmacodynamics: Formerly known as FK463, micafungin is a semisynthetic lipopeptide synthesized from a fermentation product of Coleophoma empetri that works as an antifungal agent. It is a glucan synthesis inhibitor of the echinocandin structural class. The U. S. Food and Drug Administration approved micafungin in March 2005. Micafungin inhibits an enzyme essential for fungal cell-wall synthesis. Depending on its concentration, micafungin may be fungicidal against some Candida, but is usually fungistatic against Apergillus. Micafungin can be used concomitantly with a variety of other drugs, including the HIV protease inhibitor ritonavir and the transplant medications cyclosporine and tacrolimus. 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 Micafungin is that it Micafungin inhibits the synthesis of beta-1,3-D-glucan, an essential component of fungal cell walls which is not present in mammalian cells. It does this by inhibiting beta-1,3-D-glucan synthase. Acenocoumarol absorption: Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration. Micafungin absorption: Not absorbed orally. 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 Micafungin is 0. 39 ± 0. 11 L/kg [adult patients with esophageal candidiasis]. Acenocoumarol is 98. 7% protein bound, mainly to albumin bound to plasma proteins. Micafungin is Highly (>99%) protein bound in vitro, independent of plasma concentrations over the range of 10 to 100 µg/mL. The primary binding protein is albumin; however, micafungin, at therapeutically relevant concentrations, does not competitively displace bilirubin binding to albumin. Micafungin also binds to a lesser extent to a 1 -acid-glycoprotein. 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. Micafungin metabolism: Micafungin is metabolized to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol-O-methyltransferase. M-5 is formed by hydroxylation at the side chain (w-1 position) of micafungin catalyzed by cytochrome P450 (CYP) isozymes. Even though micafungin is a substrate for and a weak inhibitor of CYP3A in vitro, hydroxylation by CYP3A is not a major pathway for micafungin metabolism in vivo. Acenocoumarol is eliminated via Mostly via the kidney as metabolites. Micafungin is eliminated via Fecal excretion is the major route of elimination (total radioactivity at 28 days was 71% of the administered dose). The half-life of Acenocoumarol is 8 to 11 hours. The half-life of Micafungin is 14-17 hours. No clearance information is available for Acenocoumarol. The clearance of Micafungin is 0. 359 +/- 0. 179 mL/min/kg [Adult Patients with IC with 100 mg]. 0. 321 +/- 0. 098 mL/min/kg [HIV- Positive Patients with EC with 50 mg] 0. 327 +/- 0. 093 mL/min/kg [HIV- Positive Patients with EC with 100 mg] 0. 340 +/- 0. 092 mL/min/kg [HIV- Positive Patients with EC with 150 mg] 0. 214 +/- 0. 031 mL/min/kg [hematopoietic stem cell transplant recipients 3 mg/kg] 0. 204 +/- 0. 036 mL/min/kg [hematopoietic stem cell transplant recipients 4 mg/kg] 0. 224 +/- 0. 064 mL/min/kg [hematopoietic stem cell transplant recipients 6 mg/kg] 0. 223 +/- 0. 081 mL/min/kg [hematopoietic stem cell transplant recipients 8 mg/kg] 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. Micafungin toxicity includes Intravenous LD 50 in rats is 125mg/kg. In dogs it is >200mg/kg. No cases of overdosage have been reported. Repeated daily doses up to 8 mg/kg (maximum total dose of 896 mg) in adult patients have been administered in clinical trials with no reported dose-limiting toxicity. The minimum lethal dose is 125 mg/kg in rats, equivalent to 8. 1 times the recommended human clinical dose for esophageal candidiasis based on body surface area comparisons. Brand names of Acenocoumarol include No brand names available. Brand names of Micafungin include Mycamine. No synonyms are available for Acenocoumarol. Acénocoumarol Acenocoumarol Acenocoumarolum Acenocumarol Acenocumarolo Acenokumarin Nicoumalone Nicumalon Nitrovarfarian Nitrowarfarin No synonyms are available for Micafungin. 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. Micafungin summary: It is Micafungin is an antifungal agent used for the treatment of candidemia, acute disseminated candidiasis, and certain other invasive Candida infections, and for the prophylaxis of Candida infections during stem cell transplantation. Answer: There have been reports of changes in INR with concomitant use of antfungal agents and vitamin K antagonists although no consistent clinical effects have been established. This may be due to reduced metabolism through a cytochrome P450-mediated pharmacokinetic interaction or through effects on production of vitamin K by gut flora.

Acenocoumarol

Drug A is Anakinra. Drug B is Dabrafenib. The severity of the interaction is major. The metabolism of Dabrafenib 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 CYP2C8 substrates with a narrow therapeutic index. 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. Dabrafenib is indicated for As monotherapy, dabrafenib is indicated to treat unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. In combination with trametinib, dabrafenib is indicated to treat for: the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. the adjuvant treatment of melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection. the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation. the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options. treatment of adult and pediatric patients six years and older with unresectable or metastatic solid tumours with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on the overall 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). the treatment of pediatric patients one year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. Dabrafenib has limitations of use: it is neither indicated for treating patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition nor wild-type BRAF solid tumours. 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. Dabrafenib pharmacodynamics: Dabrafenib is a kinase inhibitor that is mainly used to target BRAF V600E mutation in multiple types of cancer. Although dabrafenib and trametinib both inhibit the RAS/RAF/MEK/ERK pathway, they inhibit different effectors of the pathway, thus increasing response rate and mitigating resistance without cumulative toxicity. The melanoma approval for use with trametinib is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with dabrafenib + trametinib after complete surgical resection. Patients received doses of dabrafenib (150 mg BID) + trametinib (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2. 8 years, the primary endpoint of relapse-free survival (RFS) was met. In the case of thyroid cancer, Dabrafenib plus Trametinib is the first regimen demonstrated to have potent clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and is well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease. 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 Dabrafenib is that it Dabrafenib is a competitive and selective BRAF inhibitor by binding to its ATP pocket. Although dabrafenib can inhibit wild-type BRAF, it has a higher affinity for mutant forms of BRAF, including BRAF V600E, BRAF V600K, and BRAF V600D. BRAF is a serine/threonine protein kinase and is involved in activating the RAS/RAF/MEK/ERK or MAPK pathway, a pathway that is implicated in cell cycle progression, cell proliferation, and arresting apoptosis. Therefore, constitutive active mutation of BRAF such as BRAF V600E is frequently observed in many types of cancer, including melanoma, lung cancer, and colon cancer. 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. Dabrafenib absorption: After oral administration, the median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95%. Following a single dose, dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner across the dose range of 12 mg to 300 mg, but the increase was less than dose-proportional after repeat twice-daily dosing. After repeated twice-daily dosing of 150 mg, the mean accumulation ratio was 0. 73, and the inter-subject variability (CV%) of AUC at steady-state was 38%. 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 Dabrafenib is The apparent volume of distribution (Vc/F) is 70. 3 L. Distribution to the brain is restricted because dabrafenib is a substrate and undergoes efflux by P-glycoprotein and breast cancer resistance protein. No protein binding information is available for Anakinra. Dabrafenib is Dabrafenib is 99. 7% 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. Dabrafenib metabolism: The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites. 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. Dabrafenib is eliminated via Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only. 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 Dabrafenib is The mean terminal half-life of dabrafenib is 8 hours after oral administration. Hydroxy-dabrafenib's terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours). 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 Dabrafenib is The clearance of dabrafenib is 17. 0 L/h after single dosing and 34. 4 L/h after 2 weeks of twice-daily dosing. 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. Dabrafenib toxicity includes Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials. Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay and was not clastogenic in an in vivo rat bone marrow micronucleus test. In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended dose based on AUC). Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended dose based on AUC, respectively. Brand names of Anakinra include Kineret. Brand names of Dabrafenib include Tafinlar. No synonyms are available for Anakinra. No synonyms are available for Dabrafenib. 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). Dabrafenib summary: It is Dabrafenib is a kinase inhibitor used to treat patients with specific types of melanoma, non-small cell lung cancer, and thyroid cancer. 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 CYP2C8 substrates with a narrow therapeutic index.

Anakinra

Drug A is Botulinum toxin type A. Drug B is St. John's Wort. The severity of the interaction is moderate. The risk or severity of CNS depression can be increased when Botulinum toxin type A is combined with St. John's Wort. 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. Botulinum toxin type A is indicated for Botulinum toxin A is indicated for a variety of conditions, depending on the preparations. Cosmetically, it is used for the treatment of facial fine lines and wrinkles, specifically for upper facial rhytides, including forehead, lateral canthus, and glabellar lines. In addition to the above indications, botulinum toxin A is used for the following conditions: treatment of adults with symptomatic overactive bladder with or without incontinence, treatment of incontinence in adult patients who are not candidates for anticholinergic therapy, treatment of Neurogenic Detrusor Overactivity (NDO) in patients over 5 years who cannot undergo anticholinergic therapy. Botulinum toxin A is indicated for the prevention of chronic migraines, for the treatment of muscle spasms, cervical dystonia, axillary hyperhidrosis, strabismus, and disorders of the 7th cranial nerve. Off-label, botulinum toxin A is used for a variety of conditions such as temporomandibular joint (TMJ) disorders and myofascial pain, neurogenic thoracic outlet syndrome, epicondylitis, post-stroke pain, post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, neuropathic pain, spinal cord injury, and bladder pain. Botulinum toxin type A pharmacodynamics: Botulinum toxin A inhibits the release of acetylcholine, relieving muscle contraction and spasm associated with many conditions, such as incontinence and dystonia. Cosmetically, botulinum toxin A paralyses muscles in the face to temporarily treat wrinkles. The maximum effects of muscle paralysis occur four to seven days after a dose. When injected at therapeutic doses, botulinum toxin A causes partial chemical denervation of muscle tissue, causing local reduction of muscle activity. Muscle atrophy may result, axonal sprouting may begin, and extrajunctional acetylcholine receptors can be formed. Reinnervation of the muscle may occur, reversing muscle denervation caused by botulinum toxin A. The mechanism of action of Botulinum toxin type A is that it Botulinum toxin is a 150-kDa molecular weight protein consisting of a light chain (50 kDa) and heavy chain (100 kDa) linked by a single disulfide bond. The crystal structure reveals 3 lobes - the light chain, the amino-terminal portion of the heavy chain, and the carboxyl-terminal portion of the heavy chain. Botulinum toxin type A blocks neuromuscular transmission on motor or sympathetic nerve terminals, inhibiting the release of acetylcholine. Botulinum toxins have actions on various regions: the neuromuscular junction, autonomic ganglia, and both postganglionic sympathetic and parasympathetic nerve endings. The heavy chain of the toxin binds selectively at the presynaptic surface of cholinergic neurons in an irreversible fashion. After binding, the toxin-receptor complex is transported into the cell by endocytosis. The disulfide bond between the two chains is cleaved and the botulism toxin enters the cytoplasm. The light chain specifically interacts with SNAP-25 in the nerve terminals to block binding of acetylcholine vesicles with the cell membrane. SNAP-25 is required for successful binding and release of acetylcholine from vesicles in nerve endings. Botulinum toxin type A absorption: The chemical complexity of botulinum toxin type A combined with its extreme potency limits the opportunity to study its pharmacokinetic profile in humans. For this reason, human pharmacokinetic studies have not been performed. Animal studies using radio labeled botulinum toxin suggest it is absorbed systemically after subcutaneous and intranasal administration. Clinical relevance is unknown. The volume of distribution of Botulinum toxin type A is There are extremely limited data about the pharmacokinetics of botulinum toxin in humans. An animal study demonstrated that botulinum toxin accumulates in the liver and spleen in rats and mice when injected subcutaneously or administered intranasally. Botulinum toxin type A is A pharmacokinetic study in mice and rats revealed significant binding to albumin after subcutaneous injection or intranasal administration. bound to plasma proteins. Botulinum toxin type A metabolism: Metabolism information for botulinum A toxin is not readily available in the literature. Botulinum toxin type A is eliminated via Elimination information for botulinum A toxin is not readily available in the literature. The half-life of Botulinum toxin type A is There is no readily available data about the pharmacokinetics of botulinum toxin in humans. The elimination half-life for non-metabolized botulinum toxin in blood and serum ranged from 230 to 260 min in a pharmacokinetic study of rats and mice. The clearance of Botulinum toxin type A is Clearance information for botulinum A toxin is not readily available in the literature. Botulinum toxin type A toxicity includes The intraperitoneal LD50 of botulinum toxin A in mice is 160 ng/kg. An overdose of botulinum toxin A is expected to produce neuromuscular weakness, manifested by a variety of symptoms that may not appear immediately after injection. Dysphagia, dysphonia, weakness, dyspnea or respiratory distress may indicate distant spread of botulinum toxin A effects. If an overdose is suspected or confirmed, patients should be monitored for several weeks closely for local and distant neurologic effects. Hospitalization or further medical evaluation and appropriate intervention should be provided immediately. Brand names of Botulinum toxin type A include Botox, Botox Cosmetic, Dysport, Xeomin. No synonyms are available for Botulinum toxin type A. Botulinum toxin type A summary: It is Botulinum toxin type A is a purified form of botulinum toxin type A used to block acetylcholine release in the treatment of chronic sialorrhea, muscle spasticity, and dystonia, as well as in cosmetic applications. St. John's Wort summary: It is Summary not found. 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.

Botulinum toxin type A

Drug A is Bimekizumab. Drug B is Dihydroergocristine. The severity of the interaction is moderate. The metabolism of Dihydroergocristine 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 CYP3A4 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. Dihydroergocristine is indicated for Dihydroergocristine is used in some countries such as Brasil as a single agent for the treatment of cerebral and peripheric vascular events. To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate. 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. Dihydroergocristine pharmacodynamics: Dihydroergocristine has been shown to present effect on memory and cognition. This activity in the brain is been reported by an increase in glutathione in age-related brain states. The reported effect on serotonin and adrenergic receptors has also been correlated to an inhibition of platelet aggregation. It has also been reported that individuals exposed to dihydroergocristine may present an amphoteric vasoregulating activity either hypotensive in hypertensive individuals or hypertensive in hypotensive individuals. This action is performed by promoting a dilating action in the contracted arteries and a tonic action in the dilated arteries and arterioles. The vasoregulating effect causes an increase in cerebral blood flow and oxygen consumption by the brain, which correlates with the brain protective function of dihydroergocristine. In Alzheimer studies, dihydroergocristine reduced the amyloid-beta levels in different cell types. To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate. 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 Dihydroergocristine is that it Dihydroergocristine mechanism of action seems to be related to a noncompetitive antagonistic activity in the serotonin receptors as well as a double partial agonist/antagonist activity in dopaminergic and adrenergic receptors. In Alzheimer studies, dihydroergocristine act as a direct inhibitor of γ-secretase. Bimekizumab absorption: In healthy volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70. 1%. Dihydroergocristine absorption: Dihydroergocristine presents an absorption in the digestive tract of about 25% of the administered dose. When dihydroergocristine was orally administered in humans and the peak plasma concentration of 0. 28 mcg/l was achieved after 0. 46 hours. In the same report, the AUC was reported to be 0. 39 mcg/l. h. To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate. The volume of distribution of Bimekizumab is In patients with plaque psoriasis, the median volume of distribution at steady-state was 11. 2 L. The volume of distribution of Dihydroergocristine is Dihydroergocristine presents a large volume of distribution of 52 l/kg. To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate. No protein binding information is available for Bimekizumab. Dihydroergocristine is Dihydroergocristine can be found in a bound state to plasma proteins in a proportion of even 68% of the administered dose. To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate. bound to plasma proteins. Bimekizumab metabolism: As a monoclonal antibody, bimekizumab is likely degraded into smaller peptides and amino acids via catabolic processes. Dihydroergocristine metabolism: The major metabolite of dihydroergocristine is 8'-hydroxy-dihydroergocristine is produced in the liver. The modification of dihydroergocristine in the body is very extensive and it has been observed as an almost complete absence of the unchanged drug. To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate. Bimekizumab is eliminated via No route of elimination available. Dihydroergocristine is eliminated via The most important elimination route of dihydroergocristine is in via the bile and it accounts for over 85% of the eliminated dose. Urine elimination accounts only for 5% of the administered dose. To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate. 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 Dihydroergocristine is The half-life of dihydroergocristine has only been studied as part of the therapeutic mixture, please refer to Ergoloid mesylate. The clearance of Bimekizumab is The median apparent clearance of bimekuzmab in patients with plaque psoriasis was 0. 337 L/day. The clearance of Dihydroergocristine is Dihydroergocristine presents a high systemic clearance rate of 2. 65 l/h. hg. To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate. 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. Dihydroergocristine toxicity includes Studies related to acute and chronic toxicity as well as teratogenesis and fertility has proven that dihydroergocristine is a non-toxic and very well tolerated drug. To know more about dihydroergocristine as part of the ergoloid mesylate mixture, please visit Ergoloid mesylate. Brand names of Bimekizumab include No brand names available. Brand names of Dihydroergocristine include No brand names available. No synonyms are available for Bimekizumab. No synonyms are available for Dihydroergocristine. Bimekizumab summary: It is Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment plaque psoriasis. Dihydroergocristine summary: It is Dihydroergocristine is an ergot alkaloid used to delay progressive mental decline in conditions like Alzheimer's. 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.

Bimekizumab

Drug A is Acebutolol. Drug B is Duloxetine. The severity of the interaction is minor. The risk or severity of orthostatic hypotension and syncope can be increased when Acebutolol is combined with Duloxetine. Cases of orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine, which may occur anytime during therapy, particularly within the first week of therapy. The risk of developing decreased blood pressure may increase with the concomitant use of other agents known to cause hypotension. Acebutolol is indicated for the management of hypertension and ventricular premature beats in adults. Duloxetine is indicated for Indicated for: 1) Management of Major Depressive Disorder. 2) Management of Generalized Anxiety Disorder. 3) Management of diabetic peripheral neuropathy. 4) Management of fibromyalgia. 5) Management of chronic musculoskeletal pain. 6) Management of osteoarthritis of the knee in adults. 7) Management of chronic lower back pain in adults. 8) Management of stress urinary incontinence in adult women. Off-label uses include: 1) Management of chemotherapy-induced peripheral neuropathy. 2) Management of stress urinary incontinence in adult men after prostatectomy until recovery is complete. 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. Duloxetine pharmacodynamics: Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter. This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores. It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg. Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the serotonergic and adrenergic pathways involved in descending inhibition of pain. This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys. While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained. Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling. 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 Duloxetine is that it Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT 2, 5-HT 3, and α 1 adrenergic receptors. 5-HT 2 and α 1 are both G q coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP 3 /PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT 3 functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate. Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 2, 5-HT 3, α 1 -adrenergic, and α 2 -adrenergic receptors. 5-HT 2, 5-HT 3, and α 1 -adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT 1 and α 2 receptors are G i /G o coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli. The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed. Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α 1 receptors predominates, vasoconstriction results as the G q coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction. Acebutolol absorption: Well absorbed from the Gl tract with an absolute bioavailability of approximately 40% for the parent compound. Duloxetine absorption: Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%. The population absorption constant (ka) is 0. 168 h. The molecule is susceptible to hydrolysis in acidic environments necessitating the use of an enteric coating to protect it during transit through the stomach. This creates a 2 hour lag time from administration to the start of absorption. The Tmax is 6 hours including the lag time. Administering duloxetine with food 3 hour delay in Tmax along with an 10% decrease in AUC. Similarly, administering the dose at bedtime produces a 4 hour delay and 18% decrease in AUC with a 29% reduction in Cmax. These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree. No volume of distribution information is available for Acebutolol. The volume of distribution of Duloxetine is Apparent Vd of 1620-1800 L. Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma. Acebutolol is 26% bound to plasma proteins. Duloxetine is Over 90% bound to plasma proteins, primarily albumin and α1 acid-glycoprotein. bound to plasma proteins. Acebutolol metabolism: Subject to extensive first-pass hepatic biotransformation (primarily to diacetolol). Duloxetine metabolism: Duloxetine is extensively metabolized primarily by CYP1A2 and CYP2D6 with the former being the greater contributor. It is hydroxylated at the 4, 5, or 6 positions on the naphthalene ring with the 4-hydroxy metabolite proceeding directly to a glucuronide conjugate while the 5 and 6-hydroxy metabolites proceed through a catechol and a 5-hydroxy, 6-methoxy intermediate before undergoing glucuronide or sulfate conjugation. CYP2C9 is known to be a minor contributor to the 5-hydroxy metabolite. Another uncharacterized metabolite is known to be excreted in the feces but comprises <5% of the total excreted drug. Many other metabolites exist but have not been identified due their low contribution to the overall profile of duloxetine and lack of clinical significance. 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. Duloxetine is eliminated via About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites. Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite. Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit. 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 Duloxetine is Mean of 12 h with a range of 8-17. No clearance information is available for Acebutolol. The clearance of Duloxetine is There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h. Steady state concentrations have still been shown to be dose proportional with a doubling of dose from 30 to 60 mg and from 60 to 120 mg producing 2. 3 and 2. 6 times the Css respectively. 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. Duloxetine toxicity includes Overdose Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone. Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and the drug is unlikely to be cleared by hemodialysis. Supportive care is recommended along with activated charcoal and gastric lavage to reduce absorption. If serotonin syndrome occurs specific treatment such as temperature control or cyproheptadine may be initiated. Carcinogenicity & Mutagenicity Increased incidence of hepatocellular carcinomas and adenomas were reported in female mice fed 140 mg/kg/day duloxetine for 2 years, equivalent to 6 times the maximum recommended human dose (MRHD). No effect was reported with doses of 50mg/kg/day (2 time MRHD) in females or 100 mg/kg/day in males (4 times MRHD). Similar investigation in rats produced no carcinogenicity at doses of 27 mg/kg/day (2 times MRHD)in females and 36 mg/kg/day in males (4 times MRHD). No mutagenicity, clastogenicity, induction of sister chromatid exchange, or genotoxicity has been observed in toxicology investigations. Reproductive Toxicity Neither male or female rats displayed adverse reproductive effects at doses up to 45 mg/kg/day (4 times MRHD). Lactation An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0. 14% of the maternal dose. Breast milk concentrations have been observed to peak 3 hours after administration. Brand names of Acebutolol include Sectral. Brand names of Duloxetine include Cymbalta, Drizalma, Irenka, Yentreve. No synonyms are available for Acebutolol. Acebutololum Acetobutolol No synonyms are available for Duloxetine. Duloxetina Duloxetine Acebutolol summary: It is Acebutolol is a selective β1-receptor antagonist used for the management of hypertension and ventricular premature beats in adults. Duloxetine summary: It is Duloxetine is a serotonin norepinephrine reuptake inhibitor used to treat generalized anxiety disorder, neuropathic pain, osteoarthritis, and stress incontinence. Answer: Cases of orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine, which may occur anytime during therapy, particularly within the first week of therapy. The risk of developing decreased blood pressure may increase with the concomitant use of other agents known to cause hypotension.

Acebutolol

Drug A is Acetylsalicylic acid. Drug B is Salmeterol. The severity of the interaction is minor. The risk or severity of hypertension can be increased when Salmeterol is combined with Acetylsalicylic acid. Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity. Salmeterol is indicated for Salmeterol is indicated in the treatment of asthma with an inhaled corticosteroid, prevention of exercise induced bronchospasm, and the maintenance of airflow obstruction and prevention of exacerbations of chronic obstructive pulmonary disease. Salmeterol pharmacodynamics: Salmeterol is a long acting beta-2 adrenergic receptor agonist that binds to both the active and exo sites of the beta-2 adrenergic receptor. Salmeterol has a longer duration of action than other beta-2 agonists like salbutamol. Patients should be counselled regarding the risks of long acting beta agonist (LABA) monotherapy, hypokalemia, hypoglycemia, and not to take this drug with another LABA. The mechanism of action of Salmeterol is that it Beta-2 adrenoceptor stimulation causes relaxation of bronchial smooth muscle, bronchodilation, and increased airflow. Salmeterol is hypothesized to bind to 2 sites on the beta-2 adrenoceptor. The saligenin moiety binds to the active site of the beta-2 adrenoceptor. The hydrophilic tail of salmeterol binds to leucine residues in the exo-site of the beta-2 adrenoceptor almost irreversibly, allowing salmeterol to persist in the active site, which is responsible for it's long duration of action. Another hypothesis is that the lipophilic drug diffuses into lipid bilayer of smooth muscle cells and provides a depot of drug to the cells over a longer period of time. Salmeterol absorption: In asthmatic patients, a 50µg dose of inhaled salmeterol powder reaches a Cmax of 47. 897pg/mL, with a Tmax of 0. 240h, and an AUC of 156. 041pg/mL/h. The volume of distribution of Salmeterol is In asthmatic patients, the volume of distribution of the central compartment is 177L and the volume of distribution of the peripheral compartment is 3160L. Salmeterol is Salmeterol is 96% protein bound in plasma to albumin and alpha-1-acid glycoprotein. bound to plasma proteins. Salmeterol metabolism: Salmeterol is predominantly metabolized by CYP3A4 to alpha-hydroxysalmeterol, and minorly by an unknown mechanism to an O-dealkylated metabolite. Salmeterol is eliminated via Salmeterol is 57. 4% eliminated in the feces and 23% in the urine. Less than 5% of a dose is eliminated in the urine as unchanged salmeterol. The half-life of Salmeterol is The half life of salmeterol is 5. 5h. The clearance of Salmeterol is The average clearance of salmeterol in a group of asthmatic patients was 392L/h. Further data regarding the clearance of salmeterol is not readily available. Salmeterol toxicity includes Patients experiencing an overdose have presented with metabolic acidosis, hyperlactatemia, anxiety, palpitations, chest pain, sinus tachycardia, ST depression, hypokalemia, hypophosphatemia. Though patients may also present with seizures, angina, hypertension or hypotension, arrhythmia, headache, tremor, muscle cramps, dry mouth, nausea, dizziness, fatigue, malaise, insomnia, and hyperglycemia. Patients should be given symptomatic and supportive treatment which may include intravenous fluids, potassium supplementation, a cardioselective beta-blocker, and cardiac monitoring. Data regarding the LD 50 of salmeterol is not readily available. Brand names of Salmeterol include Advair, Airduo, Airduo Respiclick, Serevent, Serevent Diskus, Wixela. No synonyms are available for Salmeterol. Acetylsalicylic acid summary: It is Summary not found. Salmeterol summary: It is Salmeterol is a long-acting beta-2 adrenergic receptor agonist used to treat asthma and COPD. Answer: Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity.

Acetylsalicylic acid

Drug A is Antithrombin Alfa. Drug B is Synthetic Conjugated Estrogens, B. The severity of the interaction is moderate. Synthetic Conjugated Estrogens, B may decrease the anticoagulant activities of Antithrombin Alfa. 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. 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. Synthetic Conjugated Estrogens, B is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause and for the treatment of moderate to severe vaginal dryness, pain with intercourse, and symptoms of vulvar and vaginal atrophy due to menopause. 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. Synthetic Conjugated Estrogens, B pharmacodynamics: No pharmacodynamics available. 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 Synthetic Conjugated Estrogens, B is that it All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT). Antithrombin Alfa absorption: Given IV so not absorbed. Synthetic Conjugated Estrogens, B absorption: Synthetic conjugated estrogens, B are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The tablets release synthetic conjugated estrogens, B slowly over a period of several hours. 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. The volume of distribution of Synthetic Conjugated Estrogens, B 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. Antithrombin Alfa is Binds and inhibits thrombin and factor Xa. bound to plasma proteins. Synthetic Conjugated Estrogens, B is Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. bound to plasma proteins. Antithrombin Alfa metabolism: Not metabolized. Synthetic Conjugated Estrogens, B 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 intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Antithrombin Alfa is eliminated via Irreversible complexes formed between antithrombin III and its target protease are rapidly removed by the liver. Synthetic Conjugated Estrogens, B is eliminated via Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. 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 Synthetic Conjugated Estrogens, B is The half life of baseline-corrected estrone and equilin was found to be 23. 46 hr and 15. 09 hr, respectively. 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 Synthetic Conjugated Estrogens, B. Antithrombin Alfa toxicity includes Highest dose tested was 360mg/kg/day in rats resulted in transient limb swelling. No toxicity information is available for Synthetic Conjugated Estrogens, B. Brand names of Antithrombin Alfa include Atryn. Brand names of Synthetic Conjugated Estrogens, B include Enjuvia. No synonyms are available for Antithrombin Alfa. No synonyms are available for Synthetic Conjugated Estrogens, B. Antithrombin Alfa summary: It is Antithrombin Alfa is a recombinant antithrombin used to treat peri-operative and peripartum thromboembolic events in hereditary antithrombin deficiency. Synthetic Conjugated Estrogens, B summary: It is Synthetic Conjugated Estrogens, B is a mixture of estrogens used to treat a variety of postmenopausal symptoms, including vaginal dryness. 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.

Antithrombin Alfa

Drug A is Abatacept. Drug B is Flunitrazepam. The severity of the interaction is moderate. The metabolism of Flunitrazepam 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 CYP2A6 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. Flunitrazepam is indicated for short-term treatment of severe insomnias, that are not responsive to other hypnotics. 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. Flunitrazepam pharmacodynamics: Flunitrazepam is a powerful hypnotic drug that is a benzodiazepine derivative. It has powerful hypnotic, sedative, anxiolytic, and skeletal muscle relaxant properties. The drug is sometimes used as a date rape drug. In the United States, the drug has not been approved by the Food and Drug Administration for medical use, and is considered to be an illegal drug. It has however been approved in the United Kingdom and other countries. 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 Flunitrazepam is that it Benzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. 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%. Flunitrazepam absorption: 50% (suppository) and 64-77% (oral). 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 Flunitrazepam. No protein binding information is available for Abatacept. No protein binding information is available for Flunitrazepam. No metabolism information is available for Abatacept. Flunitrazepam metabolism: Hepatic. Abatacept is eliminated via Kidney and liver. Flunitrazepam is eliminated via No route of elimination available. 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 Flunitrazepam is 18-26 hours. 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 Flunitrazepam. 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. Flunitrazepam toxicity includes Symptoms of overdose include confusion, coma, impaired coordination, sleepiness, and slowed reaction time. Brand names of Abatacept include Orencia. Brand names of Flunitrazepam include No brand names available. No synonyms are available for Abatacept. No synonyms are available for Flunitrazepam. 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. Flunitrazepam summary: It is Flunitrazepam is a benzodiazepine used to manage anxiety disorders and insomnia. 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 CYP2A6 substrates.

Abatacept

Drug A is Aceclofenac. Drug B is Leuprolide. The severity of the interaction is minor. Aceclofenac may decrease the excretion rate of Leuprolide 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. Leuprolide is indicated for Leuprolide is indicated for the treatment of advanced prostate cancer and as palliative treatment of advanced prostate cancer. It is also used for the treatment of pediatric patients with central precocious puberty (CPP). In combination with oral norethisterone (also known as norethindrone), leuprolide is also indicated for the initial treatment of the symptoms of endometriosis. Finally, in combination with iron supplementation, leuprolide is indicated for the preoperative hematological improvement of anemic patients with uterine leiomyomata (uterine fibroids). 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. Leuprolide pharmacodynamics: Leuprolide is a gonadotropin-releasing hormone (GnRH) analogue that functions as a GnRH receptor superagonist. After an initial spike in GnRH-mediated steroidal production, including testosterone and estradiol, prolonged use results in a significant drop in circulating steroid levels, in line with those produced through other forms of androgen-deprivation therapy (ADT). The corresponding hormonal/steroidal changes produce specific adverse effects in different patient populations. In women undergoing treatment for endometriosis or uterine leiomyomata, careful consideration regarding pregnancy status is advised. The initial increase in estradiol levels may worsen symptoms such as pain and bleeding. Long-term use of leuprolide is associated with loss of bone mineral density. Patients co-administered with norethisterone may experience sudden vision loss, proptosis, diplopia, migraine, thrombophlebitis, and pulmonary embolism and may also be at higher risk of cardiovascular disease. Patients with a history of depression may experience severe recurrence of depressive symptoms. In men undergoing palliative treatment for advanced/metastatic prostate cancer, short-term spikes in testosterone levels may cause tumour flare and associated symptoms such as bone pain, hematuria, neuropathy, bladder and/or ureteral obstruction, and spinal cord compression. In addition, patients are at increased risk of developing hyperglycemia, diabetes, and cardiovascular disease, which may manifest through myocardial infarction, stroke, cardiac death, or prolonged QT/QTc interval. In addition, Leuprolide may cause convulsions and embryo-fetal toxicity. In pediatric patients undergoing treatment for central precocious puberty (CPP), the initial steroidal spike may be associated with increased clinical signs of puberty within 2-4 weeks of treatment initiation. In addition, leuprolide may cause convulsions and psychiatric symptoms, including irritability, impatience, aggression, anger, and crying. 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 Leuprolide is that it Gonadotropin-releasing hormone (GnRH) is a naturally occurring decapeptide that modulates the hypothalamic-pituitary-gonadal (HPG) axis. GnRH binds to corresponding receptors (GnRHRs) on the anterior pituitary gonadotropes, which in turn release luteinizing hormone (LH) and follicle-stimulating hormone (FSH); these, in turn, affect the downstream synthesis and release of the sex hormones testosterone, dihydrotestosterone, estrone, and estradiol. Despite the variety of conditions indicated for treatment with leuprolide, the mechanism of action underlying efficacy is the same in all cases. As a GnRHR agonist, leuprolide binds to and initially activates downstream LH and FSH release; this initial spike in gonadotropin levels is responsible for some of the adverse effects associated with treatment. After 2-4 weeks of treatment, continuous stimulation of GnRHR results in feedback inhibition and significant downregulation of LH, FSH, and their corresponding downstream effects, producing a therapeutic benefit. These effects are reversible upon treatment discontinuation. 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. Leuprolide absorption: Leuprolide is typically administered as a single-dose long-acting formulation employing either microsphere or biodegradable solid depot technologies. Regardless of the exact formulation and initial dose strength, the Cmax is typically achieved by 4-5 hours post-injection and displays large variability in the range of 4. 6 - 212 ng/mL. Eventual steady-state kinetics are typically achieved by four weeks, with a narrower range of 0. 1 - 2 ng/mL. No studies on the effects of food on absorption have been carried out. The volume of distribution of Aceclofenac is The volume of distribution is approximately 25 L. The volume of distribution of Leuprolide is Leuprolide has an apparent steady-state volume of distribution of 27 L following intravenous bolus administration to healthy males. The volume of distribution for indicated routes of subcutaneous or intramuscular injection has not been reported. Aceclofenac is It is reported to be highly protein-bound (>99%). bound to plasma proteins. Leuprolide is Leuprolide displays in vitro binding to human plasma proteins between 43% and 49%. 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. Leuprolide metabolism: Radiolabeling studies suggest that leuprolide is primarily metabolized to inactive penta-, tri-, and dipeptide entities, which are likely further metabolized. It is expected that various peptidases encountered throughout systemic circulation are responsible for leuprolide metabolism. 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. Leuprolide is eliminated via Following administration of 3. 75 mg leuprolide depot suspension to three patients, less than 5% of the initial dose was recovered as unchanged or pentapeptide metabolite in the urine. The half-life of Aceclofenac is The mean plasma elimination half-life is approximately 4 hours. The half-life of Leuprolide is Leuprolide has a terminal elimination half-life of approximately three hours. The clearance of Aceclofenac is The mean clearance rate is approximately 5 L/h. The clearance of Leuprolide is Leuprolide administered as a 1 mg intravenous bolus in healthy males has a mean systemic clearance between 7. 6 and 8. 3 L/h. 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. Leuprolide toxicity includes Leuprolide is considered extremely safe, with low dose-related toxicity and comparatively mild adverse effects. Prostate cancer patients treated with leuprolide at doses as high as 20 mg/day for two years showed no additional adverse effects compared to those receiving 1 mg/day. Brand names of Aceclofenac include No brand names available. Brand names of Leuprolide include Camcevi, Eligard, Fensolvi, Lupaneta Pack 1-month, Lupron, Lupron Depot-ped, Viadur, Zeulide Depot. No synonyms are available for Aceclofenac. Acéclofénac Aceclofenac betadex Aceclofenaco Aceclofenacum No synonyms are available for Leuprolide. Aceclofenac summary: It is No summary available. Leuprolide summary: It is Leuprolide is a peptide-based GnRH receptor superagonist used for the palliative treatment of prostate cancer, uterine leiomyomata, endometriosis, and central precocious puberty. 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 Budesonide. Drug B is Pyrantel. The severity of the interaction is moderate. The risk or severity of myopathy and weakness can be increased when Pyrantel is combined with Budesonide. Both corticosteroids and neuromuscular blocking agents have been implicated in the development of myopathy and muscle weakness. 2,1 Coadministration of corticosteroids with neuromuscular blocking agents seems to potentiate this effect, though the mechanism behind this interaction is unclear. 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. Pyrantel is indicated for the treatment of enterobiasis including roundworm (ascariasis), pinworm (enterobius) and hookworm (strongyloides) and hookworm (ancylostoma) in the pyrantel pamoate form. Pyrantel is available in various formulations for humans, dogs, and cats as the pamoate (US Pharmacopeia nomenclature) or embonate (European Pharmacopoeia nomenclature) salt, which contains 34. 7% pyrantel base combined with pamoic acid., . Pyrantel pamoate (embonate) ingested orally is effective for removal and control of ascarid and hookworm infections in puppies and dogs (adult Toxocara canis, Toxascaris leonina, Ancylostoma tubaeforme, An. braziliense, Uncinaria stenocephala), cats (adult Toxocara cati, Toxa. leonina, An. caninum, An. braziliense, U. stenocephala), horses and ponies (adult and immature Parascaris equorum, adult Strongylus vulgaris, S. edentatus, S. equinus, Cyathostomes (Triodontophorus spp., Cyathostomum spp., Cylicodontophorus spp., Cylicocyclus spp., Cylicostephanus spp., Poteriostomum spp. ), Oxyuris equi, Anoplocephala perfoliata), swine (adult Ascaris suum, Oesophagostomum dentatum), and humans (adult A. lumbricoides, Enterobius vermicularis, An. duodenale, Necator americanus). 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. Pyrantel pharmacodynamics: It has similar properties to both competitive and depolarizing neuromuscular blocking agents, which leads to the understanding of the paralytic effect of the drug has on parasites, ultimately resulting in the death of the parasite,. 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 Pyrantel is that it By promoting the release of acetylcholine, inhibiting cholinesterase, and stimulating ganglionic neurons, pyrantel serves as a depolarizing neuromuscular blocking agent in helminths. This causes extensive depolarization of the helminth muscle membrane, resulting in tension to the helminth's muscles, leading to paralysis and release of their attachment to the host organism intestinal walls. This action is unlike piperazine, which is a hyperpolarizing neuromuscular blocking agent that causes relaxation of the helminth muscles, leading to a subsequent detachment from the intestinal wall. Excretion of the parasites in the feces occurs by normal peristalsis. 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. Pyrantel absorption: Pyrantel is poorly absorbed from the GI tract of humans,. Peak serum concentrations occur 1–3 hours after a single dose. The volume of distribution of Budesonide is The volume of distribution of budesonide is 2. 2-3. 9L/kg. No volume of distribution information is available for Pyrantel. 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. No protein binding information is available for Pyrantel. 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. Pyrantel metabolism: Pyrantel is administered orally. The poor solubility of the pamoate salt offers the advantage of reduced absorption from the gastrointestinal tract and allows the drug to reach and act against parasites in the large intestine. Metabolism of pyrantel is rapid. The absorbed drug is partly metabolized in the liver. 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. Pyrantel is eliminated via Approximately 50% of an oral dose is excreted unchanged in feces; 7% excreted in urine as unchanged drug and metabolites. 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 Pyrantel is In pigs, following intravenous administration, pyrantel exhibited a half-life of 1. 75 +/- 0. 19 h. 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. No clearance information is available for Pyrantel. 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. Pyrantel toxicity includes Mild adverse effects include nausea, vomiting, diarrhea, headache, and dizziness. LD50 in rats is 535 mg/kg. Reported effects in humans in case of overdose include gastrointestinal disturbance, central nervous system effects, and superficial skin reactions. In one study, serum aspartate aminotransferase (AST) and serum alanine-aminotransferase (ALT) values were increased in approximately 2% of patients. Pyrantel should be used with caution in patients with severe malnutrition or anemia. Supportive therapy is recommended for anemic, dehydrated, or malnourished patients before administration of the drug. Pyrantel pamoate has been placed in pregnancy category C. This refers to the fact that animal studies have revealed adverse effects on the fetus (teratogenic/embryocidal, or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Data on the use of pyrantel pamoate in pregnant women are quite limited. In mass treatment programs for which the World Health Organization (WHO) has observed that the benefits of treatment outweigh the risks, WHO allows the use of pyrantel pamoate in the 2nd and 3rd trimesters of pregnancy, due to the fact that the effects of pyrantel on birth outcome are uncertain. The risk of treatment in pregnant women already known to have an infection needs to be balanced with the risk of disease progression if treatment were to be omitted. Individuals with liver disease are more susceptible to the toxicity in cases of pyrantel overexposure,. There are no data regarding the presence of pyrantel in breast milk. Pyrantel is poorly absorbed from the GI tract; therefore, excretion into breast milk may be minimal. Some experts recommend that a single dose of pyrantel therapy may be given to breastfeeding women. Brand names of Budesonide include Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris. Brand names of Pyrantel include Pronto Plus Pinworm, Pyral. No synonyms are available for Budesonide. Budesonide No synonyms are available for Pyrantel. Budesonide summary: It is Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis. Pyrantel summary: It is Pyrantel is an anthelmintic used to treat helminth infections. Answer: Both corticosteroids and neuromuscular blocking agents have been implicated in the development of myopathy and muscle weakness. 2,1 Coadministration of corticosteroids with neuromuscular blocking agents seems to potentiate this effect, though the mechanism behind this interaction is unclear.

Budesonide

Drug A is Blinatumomab. Drug B is Bezlotoxumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Blinatumomab is combined with Bezlotoxumab. 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. Blinatumomab is indicated for Blinatumomab is indicated for the treatment of adults and children with relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). It is also indicated in adults and children for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0. 1%. 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. Blinatumomab pharmacodynamics: Blinatumomab promoted peripheral T-cell redistribution at the start of infusion or dose escalation. In most patients, T-cell counts were lower in the first 1-2 days of treatment and returned to baseline levels within 7-14 days. An increase in T-cell levels, also known as T-cell expansion, was observed in a few patients. In the first treatment cycle, blinatumomab doses higher than ≥ 5 mcg/m2/day or ≥ 9 mcg/day decreased peripheral B-cell counts to 10 cells/microliter or less. During the blinatumomab-free period between treatment cycles (2 weeks), peripheral B-cell counts did not recover. The use of blinatumomab may lead to an elevation of IL-6, IL-10, and IFN-γ; however, cytokine levels return to baseline within 24 to 48 hours. Blinatumomab may lead to the development of cytokine release syndrome, neurological toxicities, infections, tumor lysis syndrome, neutropenia and febrile neutropenia, pancreatitis, leukoencephalopathy and transient elevations in liver enzymes. The use of blinatumomab can also affect a patient’s ability to drive and use machines. 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. The mechanism of action of Blinatumomab is that it Blinatumomab is a bispecific T-cell engager (BiTE) that targets CD19, an antigen expressed on the surface of B-cells, and CD3, an antigen expressed on the surface of T-cells. B-cell malignancies, such as acute lymphoblastic leukemia (ALL), express high levels of CD19, making it a therapeutic target for the treatment of these conditions. Blinatumomab recruits and activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on both benign and malignant B cells. By bringing T-cells and tumor cells together, blinatumomab induces an immune response that leads to T-cell activation and proliferation. It promotes the release of cytokines such as TNF-α, IFN-γ, IL-6, and IL-10 by T-cells, the induction of activation markers, such as CD69 and CD25, and the expression of adhesion molecules on the T-cell surface. Altogether, blinatumomab promotes the lysis of CD19+ tumor cells. 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. Blinatumomab absorption: In adult patients, the pharmacokinetic profile of blinatumomab appears to be linear between 5 to 90 mcg/m /day (equivalent to 9 to 162 mcg/day). The steady-state serum concentration (C ss ) of blinatumomab was achieved within a day of continuous intravenous infusion, and in the range tested, the mean C ss was approximately dose-proportional. At the clinical doses for the treatment of relapsed or refractory acute lymphoblastic leukemia (9 mcg/day and 28 mcg/day), the C ss was 228 (356) pg/mL and 616 (537) pg/mL, respectively. 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. The volume of distribution of Blinatumomab is Blinatumomab has a volume of distribution based on terminal phase of 4. 35 L. 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%). No protein binding information is available for Blinatumomab. Bezlotoxumab is No information is available. bound to plasma proteins. Blinatumomab metabolism: The metabolic pathway of blinatumomab has not been characterized. As a monoclonal antibody, blinatumomab is expected to be metabolized into small peptides and amino acids via catabolic pathways. Bezlotoxumab metabolism: Bezlotoxumab undergoes protein catabolism. Blinatumomab is eliminated via At clinical doses, negligible amounts of blinatumomab were excreted in the urine. Bezlotoxumab is eliminated via Bezlotoxumab is mainly eliminated by catabolism. The half-life of Blinatumomab is Blinatumomab has a half-life of 2. 10 hours. In pediatric patients, the half-life was 2. 19 hours in the first cycle of blinatumomab at the recommended dose. 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 clearance of Blinatumomab is Blinatumomab has an estimated systemic clearance of 3. 11 L/hour in patients receiving blinatumomab with continuous intravenous infusion. There is a 2-fold difference in clearance values between patients with normal renal function and those with moderate renal impairment. Pediatric patients had an estimated clearance of 1. 88 L/hour/m in the first cycle of blinatumomab at the recommended dose. 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. Blinatumomab toxicity includes Blinatumomab overdose cases have been reported, including a patient that received 133-fold the recommended therapeutic dose over a short period of time. In a study that included pediatric and adolescent patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), a patient receiving 30 mcg/m2/day of blinatumomab (higher than the maximum tolerated dose) experienced a fatal cardiac failure event in the setting of life-threatening cytokine release syndrome (CRS). The adverse reactions observed during blinatumomab overdoses included fever, tremors, and headache, consistent with those observed at the recommended dose. If a patient is experiencing an overdose, the blinatumomab product label recommends to interrupt the infusion, monitor the patient for signs of adverse reactions, and provide supportive care. Re-initiating blinatumomab at the recommended dose should be considered after all adverse reactions have been resolved and no earlier than 12 hours after the infusion is interrupted. The carcinogenic, genotoxic, and fertility effects of blinatumomab have not been evaluated. 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. Brand names of Blinatumomab include Blincyto. Brand names of Bezlotoxumab include Zinplava. No synonyms are available for Blinatumomab. No synonyms are available for Bezlotoxumab. Blinatumomab summary: It is Blinatumomab is an antineoplastic antibody used to treat CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in relapsed and refractory patients, as well as those in first or second complete remission with minimal residual disease (MRD). Bezlotoxumab summary: It is Bezlotoxumab is a monoclonal antibody used to reduce the recurrence of Clostridium difficile infections. 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.

Blinatumomab

Drug A is Abatacept. Drug B is Roflumilast. The severity of the interaction is minor. Roflumilast may increase the immunosuppressive activities of Abatacept. Roflumilast is an inhibitor of phosphodiesterase-4 (PDE4). Inhibition of PDE4 affects the migration and actions of pro-inflammatory cells including neutrophils, other leukocytes, T-lymphocytes, monocytes, macrophages, and fibroblasts. According to multiple product monographs for roflumilast, there is insufficient data regarding the safety of concomitant use of roflumilast with immunosuppressive agents. Therefore, the use of roflumilast with long-term immunosuppressive therapy is not recommended. The use of short term systemic corticosteroids with roflumilast may be appropriate. 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. Roflumilast is indicated for Oral roflumilast is indicated to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Topical cream roflumilast is indicated to treat plaque psoriasis, including intertriginous areas, in patients 12 years of age and older, while topical foam roflumilast is indicated to treat seborrheic dermatitis in adult and pediatric patients 9 years of age and older. 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. Roflumilast pharmacodynamics: Roflumilast and its active metabolite, roflumilast N-oxide, increase cyclic adenosine-3′, 5′-monophosphate (cAMP) in affected cells by inhibiting PDE4. They are highly selective for PDE4 and are effectively inactive against PDEs 1, 2, 3, 5, and 7. 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 Roflumilast is that it Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE4. Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic 3′,5′-adenosine monophosphate (cyclic AMP) metabolizing enzyme) activity leads to accumulation of intracellular cyclic AMP. The specific mechanism(s) by which roflumilast exerts its therapeutic action is not well defined. 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%. Roflumilast absorption: After a 500mcg dose, the bioavailability of roflumilast is about 80%. In the fasted state, maximum plasma concentrations are reached in 0. 5 to 2 hours, while in the fed state, Cmax is reduced by 40%, Tmax is increased by one hour, and total absorption is unchanged. Applied topically, the mean systemic exposure for roflumilast and its N-oxide metabolite in adults was 72. 7 ± 53. 1 and 628 ± 648 h∙ng/mL, respectively. The mean systemic exposure for roflumilast and its N-oxide metabolite in adolescents was 25. 1 ± 24. 0 and 140 ± 179 h∙ng/mL, respectively. 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 Roflumilast is Following a single oral dose of 500 mcg, the volume of distribution of roflumilast is approximately 2. 9 L/kg. No protein binding information is available for Abatacept. Roflumilast is Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. bound to plasma proteins. No metabolism information is available for Abatacept. Roflumilast metabolism: Roflumilast is metabolized to roflumilast N-oxide, the active metabolite of roflumilast in humans, by CYP3A4 and CYP1A2. The N-oxide metabolite is less potent than its parent drug in regards to PDE4 inhibition, but its plasma AUC is approximately 10-fold greater. Abatacept is eliminated via Kidney and liver. Roflumilast is eliminated via Roflumilast is excreted 70% in the urine as roflumilast N-oxide. 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 Roflumilast is Following oral administration, the plasma half-lives of roflumilast and roflumilast N-oxide are 17 hours and 30 hours, respectively. 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 Roflumilast is Plasma clearance of roflumilast following short-term intravenous infusion is approximately 9. 6 L/h. 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. Roflumilast toxicity includes There are no data regarding overdosage with orally administered roflumilast. Phase I studies in which roflumilast was administered at single doses up to 5000 mcg showed an increase in the incidence of headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess, and arterial hypotension. In the event of an overdose, administer support medical care as soon as possible. Hemodialysis is unlikely to be of benefit given the extensive protein binding of roflumilast. Brand names of Abatacept include Orencia. Brand names of Roflumilast include Daliresp, Zoryve. No synonyms are available for Abatacept. No synonyms are available for Roflumilast. 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. Roflumilast summary: It is Roflumilast is a selective phosphodiesterase-4 inhibitor indicated to decrease the risk of exacerbations in patients with severe chronic obstructive pulmonary disease (COPD) and to treat plaque psoriasis. Answer: Roflumilast is an inhibitor of phosphodiesterase-4 (PDE4). Inhibition of PDE4 affects the migration and actions of pro-inflammatory cells including neutrophils, other leukocytes, T-lymphocytes, monocytes, macrophages, and fibroblasts. According to multiple product monographs for roflumilast , there is insufficient data regarding the safety of concomitant use of roflumilast with immunosuppressive agents. Therefore, the use of roflumilast with long-term immunosuppressive therapy is not recommended. The use of short term systemic corticosteroids with roflumilast may be appropriate.

Abatacept

Drug A is Bupropion. Drug B is Cimetidine. The severity of the interaction is moderate. The metabolism of Bupropion can be decreased when combined with Cimetidine. The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug. Bupropion is indicated for Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e. g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. 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. Bupropion pharmacodynamics: Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1. 3 mmHg. 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 Bupropion is that it Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. 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. Bupropion absorption: Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i. e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1. 5 and 7 times that of bupropion, respectively. 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. No volume of distribution information is available for Bupropion. The volume of distribution of Cimetidine is The volume of distribution of cimetidine is reported to be 1 L/kg. Bupropion is In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. bound to plasma proteins. Cimetidine is In humans, approximately 22. 5% of cimetidine is plasma protein bound. bound to plasma proteins. Bupropion metabolism: Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. 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. Bupropion is eliminated via Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0. 5%, a finding consistent with the extensive metabolism of bupropion. Cimetidine is eliminated via Cimetidine is excreted primarily in the urine. The half-life of Bupropion is 24 hours. The half-life of Cimetidine is Cimetidine's half-life is estimated to be around 2 hours. No clearance information is available for Bupropion. The clearance of Cimetidine is Cimetidine's reported systemic clearance value is approximately 500-600 ml/min. Bupropion toxicity includes Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. 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 Bupropion include Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban. Brand names of Cimetidine include Good Sense Heartburn Relief, Tagamet. No synonyms are available for Bupropion. No synonyms are available for Cimetidine. Cimetidina Cimétidine Cimetidine Cimetidinum Bupropion summary: It is Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. Cimetidine summary: It is Cimetidine is a histamine H2 receptor antagonist used to manage GERD, peptic ulcer disease, and indigestion. Answer: The subject drug is known to be an inhibitor of CYP2C9 while the affected drug is reported to be metabolized by CYP2C9. Concomitant administration of these agents can cause an increase in the serum concentration of the affected drug due to decreased metabolism by CYP2C9, which may result in increased incidence and/or severity of adverse effects related to the affected drug.

Bupropion

Drug A is Ropeginterferon alfa-2b. Drug B is Codeine. The severity of the interaction is moderate. The risk or severity of neuropsychiatric effects can be increased when Ropeginterferon alfa-2b is combined with Codeine. Concomitant use of ropeginterferon alfa-2b and narcotics, hypnotics or sedatives can produce additive neuropsychiatric side effects. Ropeginterferon alfa-2b is indicated for Ropeginterferon alfa-2b is indicated for the treatment of adult patients with polycythemia vera. Codeine is indicated for Codeine sulfate is a form of this drug that is commonly used. It is available in tablet form and indicated for the relief of mild to moderately severe pain, where the use of an opioid analgesic is appropriate. The solution form is used by itself or combined in a syrup with other drugs and is used as a cough suppressant in adults aged 18 and above,. Ropeginterferon alfa-2b pharmacodynamics: Ropeginterferon alfa-2b acts through the interferon-alpha/beta receptor to initiate downstream JAK/STAT signalling leading to its therapeutic effects. Like other interferon alfa products, ropeginterferon alfa-2b may cause various toxicities, including endocrine, cardiovascular, pulmonary, ophthalmologic, dental/periodontal, renal, and dermatological toxicity. In addition, interferon alfa has been associated with hepatotoxicity, including increases in serum ALT, AST, GGT, and bilirubin; ropeginterferon alfa-2b is contraindicated in patients with moderate to severe (Child-Pugh B or C) hepatic impairment. Pancreatitis and colitis, including fatal ulcerative/hemorrhagic/ischemic colitis, have occurred in patients treated with interferon alfa. Significant toxicity of any kind may require treatment discontinuation. Interferon alfa treatment has decreased peripheral blood counts, including thrombocytopenia and leukopenia, and altered lipid levels, including hyperlipidemia, hypertriglyceridemia, and dyslipidemia. Hypersensitivity reactions, including anaphylaxis, may occur; ropeginterferon alfa-2b is contraindicated in hypersensitive patients and those with known hypersensitivity to other interferons. Life-threatening or fatal neuropsychiatric reactions may occur, including in patients without prior history; ropeginterferon alfa-2b is contraindicated in patients with a history of severe psychiatric disorders. Finally, ropeginterferon alfa-2b can cause fetal harm and should be used with caution in females of reproductive potential. Codeine pharmacodynamics: General effects Codeine is a weak narcotic pain reliever and cough suppressant that is similar to morphine and hydrocodone. A small amount of ingested codeine is converted to morphine in the body. Codeine increases tolerance to pain, reducing existing discomfort. In addition to decreasing pain, codeine also causes sedation, drowsiness, and respiratory depression. Antitussive activity This drug has shown antitussive activity in clinical trials and has been effective in cough secondary to tuberculosis and insomnia due to coughing. Codeine suppresses the cough reflex through a direct effect on the cough center in the medulla. Effects on intestinal motility Codeine may reduce intestinal motility through both a local and possibly central mechanism of action. This may possibly lead to constipation. The chronic use of opioids, including codeine sulfate, may lead to obstructive bowel disease, particularly in patients with underlying disorders of intestinal motility. Effects on the central nervous system Codeine phosphate is an opioid analgesic with uses similar to those of morphine, but is much less potent as an analgesic. Its primary site of action is at the mu opioid receptors distributed throughout the central nervous system. The sedative activities of codeine are less potent than those of morphine. Codeine may cause respiratory system depression by the activation of μ-opioid receptors at specific sites in the central nervous system. Effects on blood pressure This drug poses an increased risk of compromised ability to maintain blood pressure due to peripheral vasodilation and other mechanisms. Effects on chronic cancer pain and other types of pain Codeine is an opioid analgesic with similar indications to those of morphine, however, is much less potent in its pain alleviating properties. Its primary action takes place at the mu opioid receptors, which are distributed throughout the central nervous system. The average duration of action is about 4 hours. Regular dosing of opioid analgesics such as codeine in patients with severe cancer pain has been well documented to improve symptoms,. The mechanism of action of Ropeginterferon alfa-2b is that it Polycythemia vera (PV) is the most common Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), which also includes essential thrombocytopenia and myelofibrosis. PV is characterized by increased hematocrit and platelet/leukocyte counts, an increased risk for hemorrhage and thromboembolic events, and a long-term propensity for myelofibrosis and leukemia. The main driver mutation, JAK2 V617F, is present in >95% of PV patients and results in constitutive JAK/STAT signalling; other exon 12 mutations in JAK2 may also result in PV. PV results in clonal hematopoietic stem cells, such that they form endogenous erythroid colonies (EECs) in vitro. Interferon alfa-2b has been used for decades in PV despite the lack of formal approval. Although the mechanism of action is unclear, interferon alfa-2b is known to bind the interferon-alpha/beta receptor (IFNAR) and activate downstream JAK/STAT signalling. The overall result is a series of anti-proliferative, anti-angiogenic, pro-apoptotic, and immunomodulatory effects, including augmenting T-cell, macrophage, and natural killer cells. Interestingly, in vitro studies have revealed that ropeginterferon alfa-2b is specific to some extent for JAK2 -mutant EECs, a result that is in line with the reduced allelic burden observed in clinical trials. Partial and complete molecular and hematological responses have been achieved with ropeginterferon alfa-2b. The mechanism of action of Codeine is that it Although the exact mechanism of action of codeine is still unknown, it is generally thought to be mediated through the agonism of opioid receptors, particularly the mu-opioid receptors. Morphine was previously postulated to contribute to the analgesic effect of codeine due to the O-demethylation of codeine to morphine by CYP2D6. Particularly, CYP2D6 poor metabolizer did not experience the analgesic effect of codeine. However, this is unlikely to be the main mechanism of action of codeine as only 5% of codeine is metabolized to morphine. Other hypotheses also postulate that codeine-6-glucuronide, the main metabolite of codeine, mediates the analgesic effect of codeine as it not only has an affinity to the mu receptors as codeine but also can be metabolized to morphine-6-glucuronide, which was observed to be more potent than morphine. Binding to the mu receptors by codeine activates the G-proteins Gα i, causing a decrease in intracellular cAMP and Ca level. This causes hyperpolarization of nociceptive neurons, thus imparing the transmission of pain signals. Ropeginterferon alfa-2b absorption: In patients with polycythemia vera on a two-week dosing interval, the estimated steady-state C min was 1. 4-12 ng/mL, Cmax was 4. 4-31 ng/mL, and AUC was 1011-7809 ng*h/mL. The estimated geometric mean (%CV) of the absorption rate constant if 0. 12 day (27%) and the estimated steady-state Cmax occurs between 2-5 days. Codeine absorption: Absorption Codeine is absorbed from the gastrointestinal tract. The maximum plasma concentration occurs 60 minutes after administration. Food Effects When 60 mg codeine sulfate was given 30 minutes post-ingestion of a high-calorie meal, there was no significant change in the absorption of codeine. Steady-state concentration The administration of 15 mg codeine sulfate every 4 hours for 5 days lead to steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) within 48 hours. The volume of distribution of Ropeginterferon alfa-2b is Ropeginterferon alfa-2b has an estimated geometric mean apparent volume of distribution (%CV) of 4. 8 L (21%) in polycythemia vera patients. The volume of distribution of Codeine is Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues. No protein binding information is available for Ropeginterferon alfa-2b. Codeine is 7-25% bound to plasma proteins. bound to plasma proteins. Ropeginterferon alfa-2b metabolism: Ropeginterferon alfa-2b is expected to be catabolized by various proteolytic enzymes. Codeine metabolism: Approximately 70 to 80% of the ingested dose of codeine is metabolized in the liver by conjugation with glucuronic acid to codeine-6­ glucuronide (C6G) and by O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major metabolic enzymes mediating the glucurodination of codeine to the metabolite, codeine 6 glucuronide. Cytochrome P450 2D6 is the major enzyme responsible for the transformation of codeine to morphine and P450 3A4 is the main enzyme mediating the conversion of codeine to norcodeine. Morphine and norcodeine are then further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and_ morphine-6-glucuronide _(M6G). Morphine and M6G have been proven to have analgesic activity in humans. The analgesic activity of C6G in humans is not known at this time. Norcodeine and M3G are generally not considered to have analgesic properties. Ropeginterferon alfa-2b is eliminated via Ropeginterferon alfa-2b is expected to be eliminated predominantly by hepatic metabolism. Codeine is eliminated via About 90% of the total dose of codeine is excreted by the kidneys. Approximately 10% of the drug excreted by the kidneys is unchanged codeine. The majority of the excretion products can be found in the urine within 6 hours of ingestion, and 40-60 % of the codeine is excreted free or conjugated, approximately 5 to 15 percent as free and conjugated morphine, and approximately 10-20% free and conjugated norcodeine. The half-life of Ropeginterferon alfa-2b is Ropeginterferon alfa-2b administered to polycythemia vera patients over a dose range of 100-500 μg has a half-life of approximately seven days. The half-life of Codeine is Plasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours. The clearance of Ropeginterferon alfa-2b is Ropeginterferon alfa-2b administered to polycythemia vera patients over a dose range of 100-500 μg has a clearance of 1. 7-2. 5 L/h. The clearance of Codeine is Renal clearance of codeine was 183 +/- 59 ml min-1 in a clinical study. Renal impairment may decrease codeine clearance. Ropeginterferon alfa-2b toxicity includes Ropeginterferon alfa-2b overdose may present with influenza-like symptoms or other adverse reactions. As there is no known antidote, symptomatic and supportive care should be administered in the result of an overdose. Ropeginterferon alfa-2b is not mutagenic in standard assays but has not been tested for carcinogenic potential. Codeine toxicity includes Oral LD50: 427 mg kg-1 (rat). Overdose/toxicity Symptoms of opioid toxicity may include confusion, somnolence, shallow breathing, constricted pupils, nausea, vomiting, constipation and a lack of appetite. In severe cases, symptoms of circulatory and respiratory depression may ensue, which may be life-threatening or fatal,. Teratogenic effects This drug is classified as a pregnancy Category C drug. There are no adequate and well-controlled studies completed in pregnant women. Codeine should only be used during pregnancy if the potential benefit outweighs the potential risk of the drug to the fetus. Codeine has shown embryolethal and fetotoxic effects in the hamster, rat as well as mouse models at about 2-4 times the maximum recommended human dose. Maternally toxic doses that were about 7 times the maximum recommended human dose of 360 mg/day, were associated with evidence of bone resorption and incomplete bone ossification. Codeine did not demonstrate evidence of embrytoxicity or fetotoxicity in the rabbit model at doses up to 2 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison. Nonteratogenic effects Neonatal codeine withdrawal has been observed in infants born to addicted and non-addicted mothers who ingested codeine-containing medications in the days before delivery. Common symptoms of narcotic withdrawal include irritability, excessive crying, tremors, hyperreflexia, seizures, fever, vomiting, diarrhea, and poor feeding. These signs may be observed shortly following birth and may require specific treatment. Codeine (30 mg/kg) given subcutaneously to pregnant rats during gestation and for 25 days after delivery increased the rate of neonatal mortality at birth. The dose given was 0. 8 times the maximum recommended human dose of 360 mg/day. The use in breastfeeding/nursing Codeine is secreted into human milk. The maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. Brand names of Ropeginterferon alfa-2b include Besremi. Brand names of Codeine include Ascomp, Cheratussin, Cheratussin Dac, Codar Ar, Codar D, Codar Gf, Codeine Contin, Covan, Damylin With Codeine, Fioricet With Codeine, Histex Ac, Linctus Codeine Blanc, M-clear Wc, M-end PE, Mar-cof BP, Mar-cof Cg, Mersyndol, Ninjacof Xg, Pseudodine C, Robaxacet-8, Robaxisal, Triacin-C, Trianal C, Triatec, Triatec-30, Triatec-8, Tusnel C, Tuxarin, Tuzistra, Tylenol With Codeine. No synonyms are available for Ropeginterferon alfa-2b. No synonyms are available for Codeine. Codeína Codéine Codeine polistirex Codeinum Methylmorphine Ropeginterferon alfa-2b summary: It is Ropeginterferon alfa-2b is a mono-pegylated type I interferon used to treat polycythemia vera. Codeine summary: It is Codeine is an opioid analgesic used to treat moderate to severe pain when the use of an opioid is indicated. Answer: Concomitant use of ropeginterferon alfa-2b and narcotics, hypnotics or sedatives can produce additive neuropsychiatric side effects.

Ropeginterferon alfa-2b

Drug A is Cetuximab. Drug B is Tocilizumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Cetuximab is combined with Tocilizumab. 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. Tocilizumab is indicated for Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. Tocilizumab is also used to treat coronavirus disease 2019 (COVID-19) in adults who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 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. Tocilizumab pharmacodynamics: Tocilizumab is an IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions. Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index. Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity. 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 Tocilizumab is that it Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts. IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and α-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin. IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation. Tocilizumab binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation. 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. Tocilizumab absorption: A 162mg subcutaneous dose given weekly has a Cmax of 51. 3±23. 2µg/mL and an AUC of 8254±3833µg*h/mL. A 162mg subcutaneous dose given every 2 weeks has a Cmax of 13±8. 3µg/mL and an AUC of 3460±2530µg*h/mL. A 162mg subcutaneous dose given every 4 weeks has a Cmax of 154±42µg/mL and an AUC of 39216±14304µg*h/mL. 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 Tocilizumab is In rheumatoid arthritis patients, the central volume of distribution is 3. 5L, the peripheral volume of distribution is 2. 9L, and the volume of distribution at steady state is 6. 4L. In giant cell arteritis patients, the central volume of distribution is 4. 09L, the peripheral volume of distribution if 3. 37L, and the volume of distribution at steady state is 7. 46L. In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1. 98L, the peripheral volume of distribution is 2. 1L, and the volume of distribution at steady state is 4. 08L. In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1. 87L, the peripheral volume of distribution is 2. 14L, and the volume of distribution at steady state is 4. 01L. Cetuximab is There is no information available. bound to plasma proteins. Tocilizumab is Data regarding the serum protein binding of tocilizumab is not readily available. bound to plasma proteins. 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. Tocilizumab metabolism: Tocilizumab, like other monoclonal antibodies, is expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes. Cetuximab is eliminated via There is limited information available. Tocilizumab is eliminated via Data regarding the exact route of elimination of monoclonal antibodies is not readily 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 Tocilizumab is The half life of tocilizumab is concentration dependent. The terminal half life in rheumatoid arthritis patients is 21. 5 days. The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 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 Tocilizumab is The linear clearance in rheumatoid arthritis patients is 12. 5mL/h, in giant cell arteritis patients is 6. 7mL/h, in polyarticular juvenile idiopathic arthritis patients is 5. 8mL/h, and in systemic juvenile idiopathic arthritis is 5. 7mL/h. Clearance is dose dependent and changes from non linear at low doses to linear at higher doses. 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. Tocilizumab toxicity includes Data regarding overdoses of tocilizumab are not readily available. Patients experiencing an overdose may develop neutropenia. In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment. Brand names of Cetuximab include Erbitux. Brand names of Tocilizumab include Actemra, RoActemra. No synonyms are available for Cetuximab. No synonyms are available for Tocilizumab. 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. Tocilizumab summary: It is Tocilizumab is an interleukin-6 (IL-6) receptor antagonist used to treat Cytokine Release Syndrome (CRS), Systemic Juvenile Idiopathic Arthritis (sJIA), Giant Cell Arteritis (GCA), and Rheumatoid Arthritis (RA). 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 Anakinra. Drug B is Sertraline. The severity of the interaction is moderate. The metabolism of Sertraline 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. Sertraline is indicated for Sertraline is indicated for the management of major depressive disorder (MDD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder (PD), premenstrual dysphoric disorder (PMDD), and social anxiety disorder (SAD). Common off-label uses for sertraline include the prevention of post stroke depression, generalized anxiety disorder (GAD), fibromyalgia, premature ejaculation, migraine prophylaxis, diabetic neuropathy, and neurocardiogenic syncope. 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. Sertraline pharmacodynamics: Sertraline improves or relieves the symptoms of depression, OCD, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, and premenstrual dysphoric disorder via the inhibition of serotonin reuptake. Clinical studies have shown that it improves cognition in depressed patients. It has less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs because it does not exert significant anticholinergic, antihistamine, or adrenergic (alpha1, alpha2, beta) blocking activity. The onset of action and beneficial effects are usually noticed after 4-6 weeks, for reasons that are not fully understood and currently under investigation. 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 Sertraline is that it Sertraline selectively inhibits the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane, thereby increasing serotonergic activity. This results in an increased synaptic concentration of serotonin in the CNS, which leads to numerous functional changes associated with enhanced serotonergic neurotransmission. These changes are believed to be responsible for the antidepressant action and beneficial effects in obsessive-compulsive (and other anxiety related disorders). It has been hypothesized that obsessive-compulsive disorder, like depression, is also caused by the disregulation of serotonin. In animal studies, chronic administration of sertraline results in down-regulation of brain norepinephrine receptors. Sertraline displays affinity for sigma-1 and 2 receptor binding sites, but binds with stronger affinity to sigma-1 binding sites. In vitro, sertraline shows little to no affinity for GABA, dopaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors. It exerts weak inhibitory actions on the neuronal uptake of norepinephrine and dopamine and exhibits no inhibitory effects on the monoamine oxidase enzyme. 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. Sertraline absorption: Following once-daily administration of 50 to 200 mg for two weeks, the mean peak plasma concentrations (Cmax) of sertraline occurred between 4. 5 to 8. 4 hours after administration, and measured at 20 to 55 μg/L. Steady-state concentrations are reached after 1 week following once-daily administration, and vary greatly depending on the patient. Bioavailability has been estimated to be above 44%. The area under the curve in healthy volunteers after a 100mg dose of sertraline was 456 μg × h/mL in one study. Effects of food on absorption The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects given a single dose with and without food. For the tablet, AUC was slightly increased when sertraline was administered with food, the Cmax was 25% greater, and the time to peak plasma concentration was shortened by about 2. 5 hours. For the oral concentrate preparation of sertraline, peak concentration was prolonged by approximately 1 hour with the ingestion of food. 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 Sertraline is Sertraline is widely distributed, and its volume of distribution is estimated to be more than 20L/kg. Post-mortem studies in humans have measured liver tissue concentrations of 3. 9–20 mg/kg for sertraline and between 1. 4 to 11 mg/kg for its active metabolite, N-desmethyl-sertraline (DMS). Studies have also determined sertraline distributes into the brain, plasma, and serum. No protein binding information is available for Anakinra. Sertraline is Sertraline is highly bound to serum proteins, at about 98%-99%. bound to plasma proteins. Anakinra metabolism: As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body. Sertraline metabolism: Sertraline is heavily metabolized in the liver and has one major active metabolite. It undergoes N-demethylation to form N-desmethylsertraline, which is much less potent in its pharmacological activity than sertraline. In addition to N-demethylation, sertraline metabolism involves N-hydroxylation, oxidative deamination, and finally, glucuronidation. The metabolism of sertraline is mainly catalyzed by CYP3A4 and CYP2B6, with some activity accounted for by CYP2C19 and CYP2D6. 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. Sertraline is eliminated via Since sertraline is extensively metabolized, excretion of unchanged drug in the urine is a minor route of elimination, with 12-14% of unchanged sertraline excreted in the feces. 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 Sertraline is The elimination half-life of sertraline is approximately 26 hours. One reference mentions an elimination half-life ranging from 22-36 hours. 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 Sertraline is In pharmacokinetic studies, the clearance of a 200mg dose of sertraline in studies of both young and elderly patients ranged between 1. 09 ± 0. 38 L/h/kg - 1. 35 ± 0. 67 L/h/kg. 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. Sertraline toxicity includes The LD50 of sertraline is >2000 mg/kg in rats according to the FDA label. One other references indicates an oral LD50 of in mice and rats of 419 - 548 mg/kg and 1327 - 1591mg/kg, respectively. The most common signs and symptoms associated with a non-fatal sertraline overdose are somnolence, vomiting, tachycardia, nausea, dizziness, agitation, and tremor. No cases of fatal overdose with only sertraline have been reported. Most fatal cases are associated with the ingestion of sertraline with other drugs. Consequences of a sertraline overdose may include serotonin syndrome, hypertension, hypotension, syncope, stupor, coma, bradycardia, bundle branch block, QT-prolongation, torsade de pointes, delirium, hallucinations, and pancreatitis. Brand names of Anakinra include Kineret. Brand names of Sertraline include Zoloft. No synonyms are available for Anakinra. No synonyms are available for Sertraline. Sertraline Sertralinum 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). Sertraline summary: It is Sertraline is a selective serotonin reuptake inhibitor (SSRI) indicated to treat major depressive disorder, social anxiety disorder and many other psychiatric conditions. 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 Botulinum toxin type B. Drug B is Clotiazepam. The severity of the interaction is moderate. The risk or severity of CNS depression can be increased when Botulinum toxin type B is combined with Clotiazepam. 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. Botulinum toxin type B is indicated for the treatment of patients with cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia. Clotiazepam is indicated for the treatment of anxiety disorders. Botulinum toxin type B pharmacodynamics: Botulinum Toxin Type B inhibits acetylcholine release at the neuromuscular junction via a three stage process: 1) Heavy Chain mediated neurospecific binding of the toxin, 2) internalization of the toxin by receptor-mediated endocytosis, and 3) ATP and pH dependent translocation of the Light Chain to the neuronal cytosol where it acts as a zinc-dependent endoprotease cleaving polypeptides essential for neurotransmitter release. Clotiazepam pharmacodynamics: Clotiazepam is a thienodiazepine possessing anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It increases the stage 2 non-rapid eye movement sleep. The mechanism of action of Botulinum toxin type B is that it Botulinum Toxin Type B binds to and cleaves the synaptic Vesicle Associated Membrane Protein (VAMP, also known as synaptobrevin) which is a component of the protein complex responsible for docking and fusion of the synaptic vesicle to the presynaptic membrane, a necessary step to neurotransmitter release. The mechanism of action of Clotiazepam is that it Clotiazepam acts at the benzodiazepine receptors (BZD). This agonizes the action of GABA, increasing the frequency of opening of the channel chlorinates and penetration of the ions chlorinates through the ionophore. Increase in membrane polarization decreases the probability of discharge of neurons. Botulinum toxin type B absorption: Though pharmacokinetic or ADME studies were not performed, Botulinum Toxin Type B is not expected to be present in the peripheral blood at measurable levels following IM injection at the recommended doses. No absorption information is available for Clotiazepam. No volume of distribution information is available for Botulinum toxin type B. No volume of distribution information is available for Clotiazepam. No protein binding information is available for Botulinum toxin type B. Clotiazepam is 99% bound to plasma proteins. bound to plasma proteins. No metabolism information is available for Botulinum toxin type B. Clotiazepam metabolism: Hepatic. Botulinum toxin type B is eliminated via No route of elimination available. Clotiazepam is eliminated via No route of elimination available. The half-life of Botulinum toxin type B is No half-life available. The half-life of Clotiazepam is 4 hours. No clearance information is available for Botulinum toxin type B. No clearance information is available for Clotiazepam. Botulinum toxin type B toxicity includes One unit of Botulinum Toxin Type B corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice. No toxicity information is available for Clotiazepam. Brand names of Botulinum toxin type B include Myobloc. Brand names of Clotiazepam include No brand names available. No synonyms are available for Botulinum toxin type B. No synonyms are available for Clotiazepam. Botulinum toxin type B summary: It is Botulinum toxin type B is a purified form of botulinum toxin type B used to block acetylcholine release in the treatment of cervical dystonia and sialorrhea. Clotiazepam summary: It is Clotiazepam is a thienodiazepine used to manage anxiety disorders 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.

Botulinum toxin type B

Drug A is Aprotinin. Drug B is Prednisolone phosphate. The severity of the interaction is minor. The therapeutic efficacy of Aprotinin can be decreased when used in combination with Prednisolone phosphate. The catabolic effects on skeletal muscle induced by corticosteroids can lead to muscle weakness and myopathy. 1 As cholinesterase inhibitors are used to improve muscle weakness in patients with myasthenia gravis, corticosteroids may attenuate this effect. Aprotinin is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion. Prednisolone phosphate is indicated for Prednisolone phosphate is indication to a number of conditions including treat allergic states, dermatologic diseases, edematous states, endocrine disorders, gastrointestinal diseases, hematologic disorders, neoplastic diseases, nervous system, ophthalmic diseases, respiratory diseases, rheumatic disorders. Aprotinin pharmacodynamics: Aprotinin is a broad spectrum protease inhibitor which modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators [e. g., kallikrein, plasmin] results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation. Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In platelets, aprotinin reduces glycoprotein loss (e. g., GpIb, GpIIb/IIIa), while in granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e. g., CD11b). The effects of aprotinin use in CPB involves a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding. Prednisolone phosphate pharmacodynamics: Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-inflammatory signals, and promoting anti-inflammatory signals. Prednisolone has a short duration of action as the half life is 2-4 hours. Corticosteroids have a wide therapeutic window as patients make require doses that are multiples of what the body naturally produces. Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections. The mechanism of action of Aprotinin is that it Aprotinin inhibits serine proteases including trypsin, chymotrypsin and plasmin at a concentration of about 125,000 IU/mL, and kallikrein at 300,000 IU/mL. The inhibition of kallikrein inhibits formation of factor XIIa. This inhibits the intrinsic pathway of coagulation and fibrinolysis. Inhibition of plasmin also slows fibrinolysis. The mechanism of action of Prednisolone phosphate 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. Aprotinin absorption: 100% (IV). Prednisolone phosphate absorption: A 30mg prednisolone oral solution reaches a Cmax of 461. 33±77. 94ng/mL with an AUC of 2426. 1±360. 0ng*h/mL. A 30mg prednisolone orally disintegrating tablet reaches a Cmax of 420. 91±78. 28ng/mL with an AUC of 2408. 1±361. 5ng*h/mL. No volume of distribution information is available for Aprotinin. The volume of distribution of Prednisolone phosphate is The volume of distribution of prednisolone phosphate has been reported as 0. 22-0. 7L/kg. No protein binding information is available for Aprotinin. Prednisolone phosphate is Prednisolone is 70-90% protein bound in plasma. Prednisolone typically binds to albumin and corticosteroid binding globulin. bound to plasma proteins. Aprotinin metabolism: Aprotinin is slowly degraded by lysosomal enzymes. Prednisolone phosphate metabolism: Prednisolone phosphate undergoes ester hydrolysis to prednisolone. After this step, the drug undergoes the normal metabolism of prednisolone. Aprotinin is eliminated via Following a single IV dose of radiolabelled aprotinin, approximately 25-40% of the radioactivity is excreted in the urine over 48 hours. After a 30 minute infusion of 1 million KIU, about 2% is excreted as unchanged drug. After a larger dose of 2 million KIU infused over 30 minutes, urinary excretion of unchanged aprotinin accounts for approximately 9% of the dose. Prednisolone phosphate is eliminated via Prednisolone is predominantly eliminated in the urine as sulfate and glucuronide conjugate metabolites. The half-life of Aprotinin is Following this distribution phase, a plasma half-life of about 150 minutes is observed. At later time points, (i. e., beyond 5 hours after dosing) there is a terminal elimination phase with a half-life of about 10 hours. The half-life of Prednisolone phosphate is The half life of prednisolone is 2-4 hours. No clearance information is available for Aprotinin. No clearance information is available for Prednisolone phosphate. No toxicity information is available for Aprotinin. Prednisolone phosphate toxicity includes Data regarding acute overdose is not readily available. However, patients experiencing chronic overdose may present with mental symptoms, moon face, abnormal fat deposits, and fluid retention. Acute oral overdose may be treated with immediate gastric lavage or emesis followed by symptomatic and supportive treatment. Chronic overdosage can be managed by temporary dose reduction or alternate day treatment. Brand names of Aprotinin include Artiss, Tisseel, Trasylol. Brand names of Prednisolone phosphate include Orapred, Pediapred. No synonyms are available for Aprotinin. No synonyms are available for Prednisolone phosphate. Prednisolone 21-phosphate Aprotinin summary: It is Aprotinin is a serine protease inhibitor used to reduce the risk for perioperative blood loss and the need for blood transfusion in high-risk patients during cardiopulmonary bypass for coronary artery bypass graft surgery. Prednisolone phosphate summary: It is Prednisolone phosphate is a corticosteroid used to treat inflammation, immune reactions, as well as endocrine or neoplastic conditions. Answer: The catabolic effects on skeletal muscle induced by corticosteroids can lead to muscle weakness and myopathy. 1 As cholinesterase inhibitors are used to improve muscle weakness in patients with myasthenia gravis, corticosteroids may attenuate this effect.

Aprotinin

Drug A is Albutrepenonacog alfa. Drug B is Edrophonium. The severity of the interaction is minor. Edrophonium may decrease the excretion rate of Albutrepenonacog alfa 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. Albutrepenonacog alfa is indicated for Under the EMA and FDA, rIX-RFP is indicated in the treatment of hemophilia B. For Health Canada, rIX-FRP is also indicated to prevent or reduce bleeding episodes. Hemophilia B is the second most common type of hemophilia. It is a rare inherited bleeding disorder caused by reduced or absent levels of factor IX (FIX). The FIX is a vitamin K-dependent plasma protease that when activated is involved in the blood coagulation cascade. The hemophilia B is caused by mutations in the FIX gene which can cause different phenotypes. The severe form is characterized by the presence of spontaneous and recurring bleeds into the joints and muscles and excessive bleeding after trauma or surgery. Edrophonium is indicated for the differential diagnosis of myasthenia gravis and as an adjunct in the evaluation of treatment requirements in this disease. It may also be used for evaluating emergency treatment in myasthenic crises. Albutrepenonacog alfa pharmacodynamics: Clinical trials with rIX-RFP in patients with moderately to severe hemophilia B demonstrated a lower annualized spontaneous, total and joint bleeding rates. It was also efficient against bleeding episodes and maintenance of hemostasis in the perioperative setting when compared with on-demand treatment. The administration of rIX-RFP presented no reports of inhibitor development. Edrophonium pharmacodynamics: Edrophonium is a short and rapid-acting anticholinesterase drug. Its effect is manifest within 30 to 60 seconds after injection and lasts an average of 10 minutes. Edrophonium's pharmacologic action is due primarily to the inhibition or inactivation of acetylcholinesterase at sites of cholinergic transmission. Nicotinic acetylcholine (nAChR)receptors are found throughout the body, especially on muscle. Stimulation of these receptors causes to muscle contraction. In myasthenia gravis the body's immune system destroys many of the nicotinic acetylcholine receptors, so that the muscle becomes less responsive to nervous stimulation. Edrophonium chloride increases the amount of acetylcholine at the nerve endings. Increased levels of acetylcholine allow the remaining receptors to function more efficiently. The mechanism of action of Albutrepenonacog alfa is that it The current therapies against hemophilia B are hampered by the short half-life of the replacement FIX therapy. Thus, to solve this problem, in rIX-RFP there is the fusion of rFIX with rAlbumin which presents a much longer half-life and it does not present interactions with the immune system. The administration of rIX-RFP increases the plasma concentration of FIX, thus addressing the coagulation deficiency of the patient. rIX-RFP is able to circulate in the plasma as an intact zymogen thanks to the pH-dependent binding to FcRn which is a normal protection pathway from lysosomal degradation of albumin. When the FIX is needed, rAlbumin is cleaved by the same proteases that activate the FIX. The mechanism of action of Edrophonium is that it Edrophonium works by prolonging the action acetylcholine, which is found naturally in the body. It does this by inhibiting the action of the enzyme acetylcholinesterase. Acetylcholine stimulates nicotinic and muscarinic receptors. When stimulated, these receptors have a range of effects. Albutrepenonacog alfa absorption: rIX-RFP absorption is very rapid as it is directly administered intravenously. In clinical trials, the maximum plasma concentration, area under the curve and mean residence time are reported to be approximately 55 IU/dL, 5500 IU. h/dL and 125 hours respectively. Edrophonium absorption: Rapidly absorbed. The volume of distribution of Albutrepenonacog alfa is The reported volume of distribution for rIX-RFP according to phase I/II and III clinical trials is 95 ml/kg. The volume of distribution of Edrophonium is 1. 6±0. 4 L/kg [Adults]. 2. 2±1. 5 L/kg [Children (0. 08-10 yrs)] 1. 8±1. 2 L/kg [Elderly (65-75 yrs)] Albutrepenonacog alfa is This pharmacokinetic value is not relevant as this drug is part of the plasma proteins. bound to plasma proteins. No protein binding information is available for Edrophonium. Albutrepenonacog alfa metabolism: The metabolism of rIX-RFP is not relevant as it is a recombinant protein and it is thought to be metabolized to peptides and amino acids. No metabolism information is available for Edrophonium. Albutrepenonacog alfa is eliminated via rIX-RFP is mainly eliminated in the urine. In preclinical studies, the distribution of urine and feces 240 hours post administration corresponded to 72. 9% and 4. 3% of the administered dose respectively. The elimination on the first 24 hours in urine and feces only corresponded to the 39. 9% and 0. 92% of the dose. Edrophonium is eliminated via Edrophonium is primarily renally excreted with 67% of the dose appearing in the urine. Hepatic metabolism and biliary excretion have also been demonstrated in animals The half-life of Albutrepenonacog alfa is The fusion of the rFIX with rAlbumin prolongs the elimination half-life of rIX-RFP in the circulation. The reported half-life in clinical trials is 92 hours. The half-life of Edrophonium is Distribution half-life is 7 to 12 minutes. Elimination half-life is 33 to 110 minutes. The clearance of Albutrepenonacog alfa is In clinical trials, the weight-adjusted clearance in children and adults is reported to be 1. 1 and 0. 9 ml/h/kg. The clearance of Edrophonium is 6. 8 +/- 2. mL/kg/min [Adults]. 6. 4 +/- 3. 9 mL/kg/min [Children (0. 08-10 yrs)] 2. 9 +/- 1. 9 mL/kg/min [Elderly (65-75 yrs)] Albutrepenonacog alfa toxicity includes rIX-RFP is very well tolerated. Mutaginicity trials were performed and they confirmed an absent mutagenic potential. Fertility studies have not been performed. Developmental studies are not of major importance as there is a very low rate of incidence of hemophilia B in females. Edrophonium toxicity includes With drugs of this type, muscarine-like symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions and bradycardia) often appear with overdosage (cholinergic crisis). Brand names of Albutrepenonacog alfa include Idelvion. Brand names of Edrophonium include Enlon, Enlon-plus. No synonyms are available for Albutrepenonacog alfa. No synonyms are available for Edrophonium. Albutrepenonacog alfa summary: It is Albutrepenonacog alfa is a recombinant Factor IX fused to recombinant human albumin used to treat hemophilia B. Edrophonium summary: It is Edrophonium is a cholinesterase inhibitor used to diagnose and evaluate myasthenia gravis. 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.

Albutrepenonacog alfa

Drug A is Bimekizumab. Drug B is Tamoxifen. The severity of the interaction is major. The metabolism of Tamoxifen 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 with a narrow therapeutic index. 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. Tamoxifen is indicated for Tamoxifen is indicated to treat estrogen receptor positive metastatic breast cancer in adults, as an adjuvant in the treatment of early stage estrogen receptor positive breast cancer in adults, to reduce the risk of invasive breast cancer after surgery and radiation in adult women with ductal carcinoma in situ. 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. Tamoxifen pharmacodynamics: Tamoxifen is a selective estrogen receptor modulator that inhibits growth and promotes apoptosis in estrogen receptor positive tumors. It has a long duration of action as the active metabolite N-desmethyltamoxifen has a half life of approximately 2 weeks. It has a narrow therapeutic index as higher doses can lead to breathing difficulty or convulsions. Tamoxifen administration is also associated with an increased incidence of uterine malignancies. 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 Tamoxifen is that it Tamoxifen competitively inhibits estrogen binding to its receptor, which is critical for it's activity in breast cancer cells. Tamoxifen leads to a decrease in tumor growth factor α and insulin-like growth factor 1, and an increase in sex hormone binding globulin. The increase in sex hormon binding globulin limits the amount of freely available estradiol. These changes reduce levels of factors that stimulate tumor growth. Tamoxifen has also been shown to induce apoptosis in estrogen receptor positive cells. This action is thought to be the result of inhibition of protein kinase C, which prevents DNA synthesis. Alternate theories for the apoptotic effect of tamoxifen comes from the approximately 3 fold increase in intracellular and mitochondrial calcium ion levels after administration or the induction of tumor growth factor β. Bimekizumab absorption: In healthy volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70. 1%. Tamoxifen absorption: An oral dose of 20mg reaches a Cmax of 40ng/mL with a Tmax of 5 hours. The metabolite N-desmethyltamoxifen reaches a Cmax of 15ng/mL. 10mg of tamoxifen orally twice daily for 3 months results in a C ss of 120ng/mL and a C ss of 336ng/mL. The volume of distribution of Bimekizumab is In patients with plaque psoriasis, the median volume of distribution at steady-state was 11. 2 L. The volume of distribution of Tamoxifen is The volume of distribution of tamoxifen is approximately 50-60L/kg. No protein binding information is available for Bimekizumab. Tamoxifen is The protein binding of tamoxifen in plasma is over 98% and mostly 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. Tamoxifen metabolism: Tamoxifen can by hydroxylated to α-hydroxytamoxifen which is then glucuronidated or undergoes sulfate conjugation by sulfotransferase 2A1. Tamoxifen can also undergo N-oxidation by flavin monooxygenases 1 and 3 to tamoxifen N-oxide. Tamoxifen is N-dealkylated to N-desmethyltamoxifen by CYP2D6, CYP1A1, CYP1A2, CYP3A4, CYP1B1, CYP2C9, CYP2C19, and CYP3A5. N-desmethyltamoxifen can be sulfate conjugated to form N-desmethyltamoxifen sulfate, 4-hydroxylated by CYP2D6 to form endoxifen, or N-dealkylated again by CYP3A4 and CYP3A5 to N,N-didesmethyltamoxifen. N,N-didesmethyltamoxifen undergoes a substitution reaction to form tamoxifen metabolite Y, followed by ether cleavage to metabolite E, which can then be sulfate conjugated by sulfotransferase 1A1 and 1E1 or O-glucuronidated. Tamoxifen can also by 4-hydroxylated by CYP2D6, CYP2B6, CYP3A4, CYP2C9, and CYP2C19 to form 4-hydroxytamoxifen. 4-hydroxytamoxifen can undergo glucuronidation by UGT1A8, UGT1A10, UGT2B7, and UGT2B17 to tamoxifen glucuronides, sulfate conjugation by sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, or N-dealkylation by CYP3A4 and CYP3A5 to endoxifen. Endoxifen undergoes demethylation to norendoxifen, a reversible sulfate conjugation reaction via sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, sulfate conjugation via sulfotransferase 2A1 to 4-endoxifen sulfate, or glucuronidation via UGT1A8, UGT1A10, UGT2B7, or UGT2B15 to tamoxifen glucuronides. Bimekizumab is eliminated via No route of elimination available. Tamoxifen is eliminated via Tamoxifen is mainly eliminated in the feces. Animal studies have shown 75% of radiolabelled tamoxifen recovered in the feces, with negligible collection from urine. However, 1 human study showed 26. 7% recovery in the urine and 24. 7% in the feces. 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 Tamoxifen is The terminal elimination half-life of tamoxifen is 5 to 7 days, while the half-life of N-desmethyltamoxifen, the primary circulating metabolite, is approximately 14 days. The clearance of Bimekizumab is The median apparent clearance of bimekuzmab in patients with plaque psoriasis was 0. 337 L/day. The clearance of Tamoxifen is The clearance of tamoxifen was 189mL/min in a study of six postmenopausal women. 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. Tamoxifen toxicity includes High doses of tamoxifen in animals lead to respiratory difficulty and convulsions. High doses in advanced metastatic cancer patients resulted in acute neurotoxicity seen by tremor, hyperreflexia, unsteady gait, and dizziness. Patients experiencing and overdose should be given supportive treatment as no specific treatment for overdose is suggested. Brand names of Bimekizumab include No brand names available. Brand names of Tamoxifen include Soltamox. No synonyms are available for Bimekizumab. No synonyms are available for Tamoxifen. Tamoxifène Tamoxifene Tamoxifeno Tamoxifenum trans-Tamoxifen Bimekizumab summary: It is Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment plaque psoriasis. Tamoxifen summary: It is Tamoxifen is a selective estrogen receptor modulator used to treat estrogen receptor positive breast cancer, reduce the risk of invasive breast cancer following surgery, or reduce the risk of breast cancer in high risk women. 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 with a narrow therapeutic index.

Bimekizumab

Drug A is Budesonide. Drug B is Felodipine. The severity of the interaction is moderate. Felodipine 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. Felodipine is indicated for the treatment of mild to moderate essential hypertension. 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. Felodipine pharmacodynamics: Felodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. It was widely accepted that CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction; however, some studies have shown that felodipine also binds to and inhibits T-type calcium channels. T-type calcium channels are most commonly found on neurons, cells with pacemaker activity and on osteocytes. The pharmacologic significance of T-type calcium channel blockade is unknown. Felodipine also binds to calmodulin and inhibits calmodulin-dependent calcium release from the sarcoplasmic reticulum. The effect of this interaction appears to be minor. Another study demonstrated that felodipine attenuates the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) by binding to the PDE-1B1 and PDE-1A2 enzyme subunits. CaMPDE is one of the key enzymes involved in cyclic nucleotides and calcium second messenger systems. Felodipine also acts as an antagonist to the mineralcorticoid receptor by competing with aldosterone for binding and blocking aldosterone-induced coactivator recruitment of the mineralcorticoid receptor. Felodipine is able to bind to skeletal and cardiac muscle isoforms of troponin C, one of the key regulatory proteins in muscle contraction. Though felodipine exhibits binding to many endogenous molecules, its vasodilatory effects are still thought to be brought about primarily through inhibition of voltage-gated L-type calcium channels. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells. 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 Felodipine is that it Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through voltage-gated L-type calcium channels. It reversibly competes against nitrendipine and other DHP CCBs for DHP binding sites in vascular smooth muscle and cultured rabbit atrial cells. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension. 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. Felodipine absorption: completely absorbed from the gastrointestinal tract; however, extensive first-pass metabolism through the portal circulation results in a low systemic availability of 15%. Bioavailability is unaffected by food. The volume of distribution of Budesonide is The volume of distribution of budesonide is 2. 2-3. 9L/kg. The volume of distribution of Felodipine is 10 L/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. Felodipine is 99%, primarily to the albumin fraction. 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. Felodipine metabolism: Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified. 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. Felodipine is eliminated via Although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta. 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 Felodipine is 17. 5-31. 5 hours in hypertensive patients; 19. 1-35. 9 hours in elderly hypertensive patients; 8. 5-19. 7 in healthy volunteers. 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 Felodipine is 0. 8 L/min [Young healthy subjects]. 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. Felodipine toxicity includes Symptoms of overdose include excessive peripheral vasodilation with marked hypotension and possibly bradycardia. Oral rat LD 50 is 1050 mg/kg. Brand names of Budesonide include Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris. Brand names of Felodipine include Plendil. No synonyms are available for Budesonide. Budesonide No synonyms are available for Felodipine. Felodipine Felodipino Felodipinum Budesonide summary: It is Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis. Felodipine summary: It is Felodipine is a calcium channel blocker used to treat hypertension. 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 Anakinra. Drug B is Agomelatine. The severity of the interaction is moderate. The metabolism of Agomelatine 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 CYP1A2 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. Agomelatine is indicated for Agomelatine is indicated to treat major depressive episodes in adults. 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. Agomelatine pharmacodynamics: Agomelatine resynchronises circadian rhythms in animal models of delayed sleep phase syndrome and other circadian rhythm disruptions. It increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal depression models, (learned helplessness test, despair test, and chronic mild stress) circadian rhythm desynchronisation, and in stress and anxiety models. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset. Controlled studies in humans have shown that agomelatine is as effective as the SSRI antidepressants paroxetine and sertraline in the treatment of major depression. 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 Agomelatine is that it The novel antidepressant agent, agomelatine, behaves as an agonist at melatonin receptors (MT1 and MT2) and as an antagonist at serotonin (5-HT)(2C) receptors. 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. Agomelatine absorption: Bioavailability is less than 5%. 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. No volume of distribution information is available for Agomelatine. No protein binding information is available for Anakinra. Agomelatine is > 95% bound to plasma proteins. Anakinra metabolism: As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body. Agomelatine metabolism: Hepatic (90% CYP1A2 and 10% CYP2C9). 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. Agomelatine 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 Agomelatine is <2 hours. 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. No clearance information is available for Agomelatine. 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 Agomelatine. Brand names of Anakinra include Kineret. Brand names of Agomelatine include Valdoxan. No synonyms are available for Anakinra. No synonyms are available for Agomelatine. 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). Agomelatine 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 CYP1A2 substrates.

Anakinra

Drug A is Necitumumab. Drug B is Ipilimumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Ipilimumab 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. 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. Ipilimumab is indicated for Ipilimumab is indicated in the following cancerous conditions: Melanoma Treatment of unresectable or metastatic melanoma in patients ≥12 years old Treatment of unresectable or metastatic melanoma, in combination with nivolumab, in adult patients Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of >1 mm who have undergone complete resection, including total lymphadenectomy Renal Cell Carcinoma (RCC) First-line treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma in combination with nivolumab Colorectal Cancer In combination with nivolumab, treatment of patients ≥12 years old with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following previous treatment with a fluoropyrimidine, oxaliplatin, and irinotecan Hepatocellular Carcinoma In combination with nivolumab, treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib Non-Small Cell Lung Cancer (NSCLC) Treatment of adult patients with metastatic non-small cell lung cancer expressing PD-L1, with no EFGR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab Treatment of adult patients with metastatic or recurrent non-small cell lung cancer, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy Malignant Pleural Mesothelioma Treatment of adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with nivolumab Esophageal Cancer - Treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma, as first line treatment in combination with nivolumab. Necitumumab pharmacodynamics: No pharmacodynamics available. Ipilimumab pharmacodynamics: Ipilimumab is a human IgG1 that binds CTLA-4, preventing 1 T-cell inhibition signal pathway. It has a long duration of action as it is given every 3 to 4 weeks. Patients should be counselled regarding the risk of immune-mediated adverse effects, infusion related reactions, and embryo-fetal toxicity. 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. The mechanism of action of Ipilimumab is that it Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule that competes with the stimulatory CD28 for binding to B7 on antigen presenting cells. CTLA-4 and CD28 are both presented on the surface of T-cells. Ipilimumab is a human IgG1 that binds CTLA-4, preventing the inhibition of T-cell mediated immune responses to tumors. No absorption information is available for Necitumumab. Ipilimumab absorption: Cmax was 65. 8µg/mL for 2-6 year olds, 70. 1µg/mL for 6-<12 year olds, and 73. 3µg/mL in patients 12 years and older. Data regarding the AUC and Tmax of ipilumumab are not readily available. The volume of distribution of Necitumumab is Steady state volume of distribution is 7. 0 L. The volume of distribution of Ipilimumab is The volume of distribution at steady-state of ipilimumab is 7. 21L. No protein binding information is available for Necitumumab. Ipilimumab is Data regarding the protein binding of ipilimumab is not readily available. bound to plasma proteins. No metabolism information is available for Necitumumab. Ipilimumab metabolism: The metabolism of ipilimumab does not involve the cytochrome P450 enzyme system. Because ipilimumab is a protein, it is expected to be degraded into small peptides and amino acids by proteolytic enzymes. Necitumumab is eliminated via No route of elimination available. Ipilimumab is eliminated via Data regarding the route of elimination of ipilimumab is not readily available. The half-life of Necitumumab is Elimination half life is approximately 14 days. The half-life of Ipilimumab is Ipilimumab has a half life of 14. 7 days. The clearance of Necitumumab is 14. 1 mL/h. The clearance of Ipilimumab is Ipilimumab has a clearance of 15. 3 mL/hr. Systemic clearance increases proportionally with body weight. 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. Ipilimumab toxicity includes Data regarding ipilumumab overdose is not readily available. However, the most common adverse reactions to ipilumumab are fatigue, diarrhea, pruritus, rash, and colitis. Brand names of Necitumumab include Portrazza. Brand names of Ipilimumab include Yervoy. No synonyms are available for Necitumumab. No synonyms are available for Ipilimumab. Necitumumab summary: It is Necitumumab is a monoclonal antibody used to treat metastatic squamous non-small cell lung cancer. Ipilimumab summary: It is Ipilimumab is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody used to treat metastatic or unresectable melanoma. 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.

Necitumumab

Drug A is Caplacizumab. Drug B is Asfotase alfa. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Caplacizumab is combined with Asfotase 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. 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. Asfotase alfa is indicated for Indicated for the treatment of patients with perinatal/infantile and juvenile onset hypophosphatasia (HPP). 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. Asfotase alfa pharmacodynamics: Perinatal/infantile- and juvenile-onset HPP patients treated with Asfotase alfa had reductions in plasma TNSALP (tissue non-specific alkaline phosphatase) substrates, PPi and pyridoxal 5'-phosphate (PLP) within 6 to 12 weeks of treatment. Reductions in plasma PPi and PLP levels did not correlate with clinical outcomes. Bone biopsy data from perinatal/infantile-onset and juvenile-onset HPP patients treated with Asfotase alfa demonstrated decreases in osteoid volume and thickness indicating improved bone mineralization. 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 Asfotase alfa is that it HPP is caused by a deficiency in TNSALP (tissue non-specific alkaline phosphatase) enzyme activity, which leads to elevations in several TNSALP substrates, including inorganic pyrophosphate (PPi). Elevated extracellular levels of PPi block hydroxyapatite crystal growth which inhibits bone mineralization and causes an accumulation of unmineralized bone matrix which manifests as rickets and bone deformation in infants and children and as osteomalacia (softening of bones) once growth plates close, along with muscle weakness. Replacement of the TNSALP enzyme upon Asfotase alfa treatment reduces the enzyme substrate levels. 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. No absorption information is available for Asfotase alfa. The volume of distribution of Caplacizumab is The reported volume of distribution of caplacizumab is 6. 33 L. No volume of distribution information is available for Asfotase alfa. Caplacizumab is This antibody acts directly on plasma proteins and thus, this parameter is not significant for drug description. bound to plasma proteins. No protein binding information is available for Asfotase alfa. Caplacizumab metabolism: Caplacizumab is degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. No metabolism information is available for Asfotase alfa. 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. Asfotase alfa is eliminated via No route of elimination 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 Asfotase alfa is Approximately 5 days. 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. No clearance information is available for Asfotase alfa. 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. Asfotase alfa toxicity includes There are no available human data on Asfotase Alfa use in pregnant women to inform a drug associated risk. In animal reproduction studies, Asfotase Alfa administered intravenously to pregnant rats and rabbits during the period of organogenesis showed no evidence of fetotoxicity, embryolethality or teratogenicity at doses causing plasma exposures up to 21 and 24 times, respectively, the exposure at the recommended human dose. Brand names of Caplacizumab include Cablivi. Brand names of Asfotase alfa include Strensiq. No synonyms are available for Caplacizumab. No synonyms are available for Asfotase alfa. Caplacizumab summary: It is Caplacizumab is a von Willebrand factor (vWF)-directed antibody fragment used to treat acquired thrombotic thrombocytopenic purpura (aTTP). Asfotase alfa summary: It is Asfotase alfa is an enzyme replacement therapy used for the treatment of perinatal/infantile and juvenile onset hypophosphatasia (HPP). 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 Anthrax immune globulin human. Drug B is Tremelimumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Tremelimumab. 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. Anthrax immune globulin human is indicated for Anthrax immune globulin is indicated for the treatment of inhalational anthrax in adult and pediatric patients in combination with appropriate antibacterial drugs. Tremelimumab is indicated for Tremelimumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma in combination with durvalumab. It is also indicated in combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Anthrax immune globulin human pharmacodynamics: No pharmacodynamics available. Tremelimumab pharmacodynamics: Tremelimumab is a cytotoxic agent that works to decrease tumour growth. It binds to its target, human CTLA-4, with high selectivity and subnanomolar affinity. Tremelimumab caused increased IL-2 production in a dose-dependent manner in ex-vivo blood stimulation assays using peripheral blood mononuclear cells (PBMCs) from healthy volunteers and patients with cancer, indicating that tremelimumab stimulated T cell-mediated cytotoxicity. Tremelimumab also increased the proliferation of effector T cells. In vitro, there was no evidence of nonspecific cytokine release induced by tremelimumab or drug binding to Fc receptors. The mechanism of action of Anthrax immune globulin human is that it Polyclonal anthrax immune globulin is a passive immunizing agent that neutralizes anthrax toxin by binding to Protective Antigen (PA) to prevent PA-mediated cellular entry of anthrax edema factor and lethal factor. It is administered in combination with appropriate antibiotic therapy as the immunoglobulin itself is not known to have direct antibacterial activity against anthrax bacteria, which otherwise may continue to grow and produce anthrax toxins. The mechanism of action of Tremelimumab is that it T cell activation is influenced by several processes. T cell receptors (TCR), which are expressed on T cells, bind to the cognate antigen processed and presented by major histocompatibility complex (MHC) expressed on antigen-presenting cells (APC). This interaction generates a TCR signal to activate T cells. In addition to the TCR signal, optimal T cell activation requires a costimulatory signal, produced when CD80 and CD86, expressed on the surface of APCs, bind to receptors expressed on T cells. CD80 and CD86 are also referred to together as B7 molecules. In response to these signals, activated T cells can be further differentiated into specific T cell subtypes with specialized functions. Immune checkpoints are proteins that control the intensity and duration of T cell activation and response. CD28 and CTLA-4 are homologous receptors expressed on CD4 and CD8 T cell surface. These immune checkpoints have opposing regulatory functions on T cell activity: CD28 is a positive regulator of T cell activity, while CTLA-4 is a negative regulator suppressing T cell activation and proliferation, as well as IL-2 gene transcription. B7 molecules act as ligands to both of these receptors, and the balance between CD28 and CTLA-4 expression and signalling influence the extent of T cell activation. In cancer immunotherapy, CTLA-4 has been investigated as a therapeutic target as blocking this receptor can enhance the activation of tumour-specific T cells, allowing them to exert cytotoxic effects on tumour cells. Tremelimumab is an antibody directed against CTLA-4. By binding to CTLA-4, tremelimumab blocks the interaction of CTLA-4 with its ligands, CD80 and CD86, limiting its negative regulatory effect on T cell activation. Inhibition of CTLA-4 leads to increased proliferation of T cells in tumours and promotes T cell-mediated cytotoxicity. Anthrax immune globulin human absorption: Peak levels were reached immediately after infusion and then declined over the duration of study (84 days). Mean activity remained above the lower limit of quantitation (5 milliunits per mL) over the entire 84-day post-dose period for the three doses studied. Cmax was found to be 83. 0 mU/mL while Tmax was found to be 0. 116 days. Tremelimumab absorption: In patients with solid tumours who received tremelimumab doses 1 mg/kg, 3 mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) once every four weeks for four doses, the AUC of tremelimumab increased proportionally and steady-state was achieved at approximately 12 weeks. The volume of distribution of Anthrax immune globulin human is 5714. 8 mL. The volume of distribution of Tremelimumab is The geometric mean (% coefficient of variation [CV%]) of tremelimumab for central (V1) and peripheral (V2) volume of distribution was 3. 45 (24%) and 2. 66 (34%) L, respectively. No protein binding information is available for Anthrax immune globulin human. No protein binding information is available for Tremelimumab. No metabolism information is available for Anthrax immune globulin human. No metabolism information is available for Tremelimumab. Anthrax immune globulin human is eliminated via No route of elimination available. Tremelimumab is eliminated via No route of elimination available. The half-life of Anthrax immune globulin human is 24. 3 days. The half-life of Tremelimumab is The geometric mean (CV%) terminal half-life of tremelimumab was 16. 9 days (19%) after a single dose and 18. 2 days (19%) during steady-state. The clearance of Anthrax immune globulin human is 174. 2 mL/day. The clearance of Tremelimumab is The geometric mean (CV%) clearance of tremelimumab was 0. 286 L/day (32%) after a single dose and 0. 263 L/day (32%) during steady-state. Anthrax immune globulin human toxicity includes The most common adverse reactions to Anthrasil observed in >5% of healthy volunteers in clinical trials were headache, infusion site pain and swelling, nausea, and back pain. Tremelimumab toxicity includes There is limited information regarding the acute toxicity profile and overdosage of tremelimumab. The maximum tolerated dose in non-human primates was 100 mg/kg. Brand names of Anthrax immune globulin human include Anthrasil. Brand names of Tremelimumab include Imjudo. No synonyms are available for Anthrax immune globulin human. No synonyms are available for Tremelimumab. Anthrax immune globulin human summary: It is Anthrax immune globulin human is an immunizing agent used for the treatment of inhalational anthrax in adult and pediatric patients in combination with antibacterial agents. Tremelimumab summary: It is Tremelimumab is an anti-CTLA-4 antibody used to treat unresectable hepatocellular carcinoma in combination with durvalumab. 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.

Anthrax immune globulin human

Drug A is Bromocriptine. Drug B is Venlafaxine. The severity of the interaction is moderate. Venlafaxine may increase the tachycardic activities of Bromocriptine. Tachycardia may be enhanced when serotonin and noradrenaline reuptake inhibitors (SNRIs) and adrenergic agonists. In addition, elevated blood pressure may result from the additive effects of both classes of drugs. Serotonin and norepinephrine in addition to adrenergic agonists act on adrenergic receptors to increase blood pressure and heart rate. 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. 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. 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. 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 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 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. 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. 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). No volume of distribution information is available for Bromocriptine. 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. Bromocriptine is 90-96% bound to serum albumin bound to plasma proteins. Venlafaxine is Venlafaxine and ODV is 27% and 30% bound to plasma proteins, respectively. 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. 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. Bromocriptine is eliminated via Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. 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 Bromocriptine is 2-8 hours. The half-life of Venlafaxine is The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV. No clearance information is available for Bromocriptine. 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. 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. 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 Bromocriptine include Cycloset, Parlodel. Brand names of Venlafaxine include Effexor. No synonyms are available for Bromocriptine. Bromocriptine Bromocriptinum Bromocryptine Bromoergocriptine Bromoergocryptine No synonyms are available for Venlafaxine. 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. 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: Tachycardia may be enhanced when serotonin and noradrenaline reuptake inhibitors (SNRIs) and adrenergic agonists. In addition, elevated blood pressure may result from the additive effects of both classes of drugs. Serotonin and norepinephrine in addition to adrenergic agonists act on adrenergic receptors to increase blood pressure and heart rate.

Bromocriptine

Drug A is Buprenorphine. Drug B is Clofarabine. The severity of the interaction is moderate. Buprenorphine may decrease the excretion rate of Clofarabine which could result in a higher serum level. Breast Cancer Resistance Protein is a ATP-binding cassette (ABC) efflux transporter that limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Pharmacokinetic interaction may occur from co-administration of drugs that are eliminated by BCRP with BCRP inhibitors that attenuate the activity of the transporter. Increased serum concentrations of and systemic exposure to BCRP substrates may result in altered therapeutic efficacy of the drug therapy and increase the risk for developing drug-related adverse reactions. 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. Clofarabine is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use. 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. Clofarabine pharmacodynamics: Clofarabine is a purine nucleoside antimetabolite that differs from other puring nucleoside analogs by the presence of a chlorine in the purine ring and a flourine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells. 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 Clofarabine is that it Clofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and 5'-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. 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 absorption information is available for Clofarabine. 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. The volume of distribution of Clofarabine is 172 L/m2. Buprenorphine is Buprenorphine is approximately 96% protein-bound, primarily to alpha- and beta-globulin. bound to plasma proteins. Clofarabine is 47% bound to plasma proteins, predominantly to albumin. bound to plasma proteins. 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. Clofarabine metabolism: Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases to the active 5’-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. 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. Clofarabine is eliminated via Based on 24-hour urine collections in the pediatric studies, 49 - 60% of the dose is excreted in the urine unchanged. 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 Clofarabine is The terminal half-life is estimated to be 5. 2 hours. 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. The clearance of Clofarabine is 28. 8 L/h/m2 [Pediatric patients (2 - 19 years old) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) receiving 52 mg/m2 dose]. Buprenorphine toxicity includes Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression and death. Clofarabine toxicity includes There were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m basis) has been 70 mg/m /day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash. Brand names of Buprenorphine include Belbuca, Brixadi, Buprenex, Buprenorphine, Butrans, Sublocade, Suboxone, Subutex, Zubsolv. Brand names of Clofarabine include Clolar, Evoltra. No synonyms are available for Buprenorphine. Buprenorfina Buprenorphine Buprenorphinum No synonyms are available for Clofarabine. Clofarabin Clofarabina Clofarabine Clofarabinum 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. Clofarabine summary: It is Clofarabine is a purine nucleoside used to treat relapsed or refractory acute lymphoblastic leukemia in patients 1 to 21 years old. Answer: Breast Cancer Resistance Protein is a ATP-binding cassette (ABC) efflux transporter that limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Pharmacokinetic interaction may occur from co-administration of drugs that are eliminated by BCRP with BCRP inhibitors that attenuate the activity of the transporter. Increased serum concentrations of and systemic exposure to BCRP substrates may result in altered therapeutic efficacy of the drug therapy and increase the risk for developing drug-related adverse reactions.

Buprenorphine

Drug A is Antihemophilic factor (recombinant), PEGylated. Drug B is Sodium citrate. The severity of the interaction is major. The therapeutic efficacy of Antihemophilic factor (recombinant), PEGylated can be decreased when used in combination with Sodium citrate. 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. 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. Sodium citrate is indicated for Used as an anticoagulant during plasmophoresis as well as a neutralizing agent in the treatment of upset stomach and acidic urine. 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,. Sodium citrate pharmacodynamics: Citrate prevents activation of the clotting cascade by chelating calcium ions. Citrate neutralizes acid in the stomach and urine, raising the pH. 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 Sodium citrate is that it Citrate chelates free calcium ions preventing them from forming a complex with tissue factor and coagulation factor VIIa to promote the activation of coagulation factor X. This inhibits the extrinsic initiation of the coagulation cascade. Citrate may also exert an anticoagulant effect via a so far unknown mechanism as restoration of calcium concentration does not fully reverse the effect of citrate. Citrate is a weak base and so reacts with hydrochloric acid in the stomach to raise the pH. It it further metabolized to bicarbonate which then acts as a systemic alkalizing agent, raising the pH of the blood and urine. It also acts as a diuretic and increases the urinary excretion of calcium. 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. Sodium citrate absorption: Tmax of 98-130min. 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 Sodium citrate is 19-39L. No protein binding information is available for Antihemophilic factor (recombinant), PEGylated. No protein binding information is available for Sodium citrate. No metabolism information is available for Antihemophilic factor (recombinant), PEGylated. Sodium citrate metabolism: Citrate is metabolized to bicarbonate in the liver and plays a role as an intermediate in the citric acid cycle. Antihemophilic factor (recombinant), PEGylated is eliminated via No route of elimination available. Sodium citrate is eliminated via Largely eliminated through hepatic metabolism with very little cleared by the kidneys. 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 Sodium citrate is 18-54 min. 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 Sodium citrate is Total clearance of 313-1107mL/min. Antihemophilic factor (recombinant), PEGylated toxicity includes Common adverse reactions reported in ≥1% of subjects in the clinical studies were headache and nausea. Sodium citrate toxicity includes Overdose toxicity is mainly due to alkalosis as well as tetany or depressed heart function due to lack of free calcium. Brand names of Antihemophilic factor (recombinant), PEGylated include Adynovate. Brand names of Sodium citrate include As 3, Bss, Bss Ophthalmic Solution, Cpda-1 Blood Collection System, Dalmacol, EnLyte, Intersol, Leukotrap, Nauzene, Oracit, Tricitrasol. No synonyms are available for Antihemophilic factor (recombinant), PEGylated. No synonyms are available for Sodium citrate. Natrocitral Trisodium citrate concentration Trisodium-citrate Antihemophilic factor (recombinant), PEGylated summary: It is No summary available. Sodium citrate summary: It is Sodium citrate is an ingredient used for the anticoagulation of whole blood as part of automated apheresis procedures. 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.

Antihemophilic factor (recombinant), PEGylated

Drug A is Aducanumab. Drug B is Bezlotoxumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Aducanumab is combined with Bezlotoxumab. 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. Aducanumab is indicated for Aducanumab is indicated for the treatment of Alzheimer’s disease. Treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. 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. Aducanumab pharmacodynamics: Aducanumab is a monoclonal IgG1 antibody that binds to amyloid-β, reducing amyloid plaques in the brain. It has a long duration of action as it is given once every 4 weeks. Patients should be counselled regarding the risk of amyloid related imaging abnormalities, including microhemorrhages, and hypersensitivity reactions. 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. The mechanism of action of Aducanumab is that it Alzheimer's disease is a neurodegenerative disease. Part of the pathology of Alzheimer's disease is the presence of plaques forming extracellularly in the brain. These plaques are mostly composed of amyloid-β, a peptide of varying length formed by the cleavage of the amyloid precursor protein. The "amyloid cascade hypothesis" suggests that the accumulation of amyloid-β oligopeptides in the brain drives the pathogenesis of Alzheimer's disease. Aducanumab is a monoclonal IgG1 antibody that binds to amyloid-β at amino acids 3-7. The amyloid-β residues Phe4, His6, Glu3, and Arg5 are responsible for the majority of the contact between amyloid-β and aducanumab's Fab region. Data from studies in mice and humans shows aducanumab treatment reduces amyloid-β, however human trials show non-significant changes in amyloid-β40 and amyloid-β42 across a dose range of 0. 3-30 mg/kg and an increase in amyloid-β40 and amyloid-β42 at 60 mg/kg. Aducanumab treatment is associated with slowing the rate of progression of Alzheimer's disease, based on Mini-Mental State Examination, Clinical Dementia Rating, and levels of p-tau in the cerebrospinal fluid. 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. Aducanumab absorption: A 10 mg/kg intravenous dose of aducanumab reached a Cmax of 182. 7 µg/mL, with a Tmax of 3. 0 hours, and an AUC inf of 31,400 h*µg/mL. 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. The volume of distribution of Aducanumab is The volume of distribution of aducanumab is 9. 63 L. 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%). No protein binding information is available for Aducanumab. Bezlotoxumab is No information is available. bound to plasma proteins. Aducanumab metabolism: Aducanumab is expected to be broken down into smaller oligopeptides and amino acids. Bezlotoxumab metabolism: Bezlotoxumab undergoes protein catabolism. Aducanumab is eliminated via Monoclonal IgG is predominantly eliminated by catabolism to individual amino acids that are either recycled in the body or metabolized for energy. Bezlotoxumab is eliminated via Bezlotoxumab is mainly eliminated by catabolism. The half-life of Aducanumab is The terminal half life of aducanumab is 24. 8 days. 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 clearance of Aducanumab is A 10 mg/kg intravenous dose of aducanumab has a clearance of 0. 39 mL/h/kg. 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. Aducanumab toxicity includes Patients experiencing dose-limiting toxicity may present with amyloid-related imaging abnormalities including edema or microhemorrhages of the brain. Symptoms of dose limiting toxicity were generally transient, however patients may need to be treated with symptomatic and supportive measures. 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. Brand names of Aducanumab include Aduhelm. Brand names of Bezlotoxumab include Zinplava. No synonyms are available for Aducanumab. No synonyms are available for Bezlotoxumab. Aducanumab summary: It is Aducanumab is a monoclonal antibody indicated in the treatment of Alzheimer's disease. Bezlotoxumab summary: It is Bezlotoxumab is a monoclonal antibody used to reduce the recurrence of Clostridium difficile infections. 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.

Aducanumab

Drug A is Corifollitropin alfa. Drug B is Methylene blue. The severity of the interaction is minor. Corifollitropin alfa may decrease the excretion rate of Methylene blue 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. Corifollitropin alfa is indicated for Controlled ovarian stimulation in cases of women who are undergoing fertility treatment to stimulate the development of more than one mature egg simultaneously in the ovaries in combination with a gonadotrophin-releasing hormone (GnRH) antagonist (a type of medicine also used in fertility treatments). Methylene blue is indicated for Indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. Other clinical applications of methylene blue include improvement of hypotension associated with various clinical states, an antiseptic in urinary tract infections, treatment of hypoxia and hyperdynamic circulation in cirrhosis of liver and severe hepatopulmonary syndrome, and treatment of ifofosamide induced neurotoxicity. Corifollitropin alfa pharmacodynamics: A single dose of corifollitropin alfa could initiate and sustain multi-follicular growth in patients undergoing controlled ovarian stimulation, such as during in vitro fertilization or intracytoplasmic sperm injection. This drug is structurally similar to follicle stimulating hormone (FSH), a hormone naturally present in females. FSH stimulates the production of eggs (ova) in the ovaries. In corifollitropin alfa, a peptide is attached to the FSH to prolong its activity. As a result, one single dose of the medicine can be administered to stimulate egg production for seven days, replacing daily injections that are normally needed with other FSH medicines. In phase III clinical trials, the number of oocytes retrieved following the administration of corifollitropin alfa was slightly higher compared with the number observed with daily recombinant FSH treatment. Methylene blue pharmacodynamics: No pharmacodynamics available. The mechanism of action of Corifollitropin alfa is that it Corifollitropin alfa is a long-lasting single injection fusion protein which lacks luteinizing hormone (LH) activity. Only one injection is needed for the first 7 days, which replaces the first 7 daily injections of traditional follicle stimulating hormone (FSH). It is a follicle-stimulation hormone (human α-subunit reduced), a combination of follicle stimulation hormone (human β-subunit reduced) fusion protein with 118-145-chorionic gonadotropin (human β-subunit). Frequent, repetitive injections increase stress and error rates, and are often a burden for women, leading to therapy noncompliance. The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH. Corifollitropin alfa serves as a sustained follicle stimulant that has similar pharmacological effects to recombinant follicle stimulating hormone (rFSH), however, with a relatively long elimination half-life, resulting in a longer duration of action. This is achieved using site-directed mutagenesis and gene transfer techniques to create a glycoprotein that consists of an α-subunit that is identical to human follicle stimulating hormone (FSH) noncovalently bound to a β-subunit comprised of a complete β-chain of human FSH elongated by the carboxyterminal peptide of the β-subunit of human chorionic gonadotrophin (hCG). This unit interacts with the FSH receptor to stimulate the release of oocytes. Corifollitropin alfa does not demonstrate any intrinsic LH/hCG activity. The mechanism of action of Methylene blue is that it Main mechanism of action involves inhibition of nitric oxide synthase and guanylate cyclase. In Alzheimers Disease: a mechanistic study found that methylene blue oxidizes cysteine sulfhydryl groups on tau to keep tau monomeric. One preclinical treatment study in tauopathy mice reported anti-inflammatory or neuroprotective effects mediated by the Nrf2/antioxidant response element (ARE); another reported insoluble tau reduction and a learning and memory benefit when given early. In Methemoglobinemia: Methylene Blue acts by reacting within RBC to form leukomethylene blue, which is a reducing agent of oxidized hemoglobin converting the ferric ion (fe+++) back to its oxygen-carrying ferrous state(fe++). As antimalarial agent: Methylene Blue, a specific inhibitor of P. falciparum glutathione reductase has the potential to reverse CQ resistance and it prevents the polymerization of haem into haemozoin similar to 4-amino-quinoline antimalarials. For ifosfamide induced neurotoxicity: Methylene blue functions as an alternate electron acceptor. It acts to reverse the NADH inhibition caused by gluconeogenesis in the liver while blocking the transformation of chloroethylamine into chloroacetaldehyde. In addition, it inhibits various amine oxidase activities, which also prevents the formation of chloroacetaldehyde. Corifollitropin alfa absorption: After one single subcutaneous injection of this drug, the maximal serum concentration is 4. 24 ng/mL (2. 49-7. 21 ng/mL1) and is reached 44 hours (35-57 h) post-dose administration. Its absolute bioavailability is 58% (48-70%). No absorption information is available for Methylene blue. The volume of distribution of Corifollitropin alfa is Distribution, metabolism and elimination of corifollitropin alfa are very similar to other gonadotropins, such as FSH, hCG and LH. After absorption into the blood, corifollitropin alfa is distributed mainly to the ovaries and the kidneys. The steady-state volume of distribution is 9. 2 L. Exposure to corifollitropin alfa increases in a linear fashion with the dose within a range of 60 micrograms - 240 micrograms. The volume of distribution of Methylene blue is 10 mg/kg (in rats). No protein binding information is available for Corifollitropin alfa. Methylene blue is Methylene blue was reported to bind strongly to rabbit plasma (71–77% of bound drug). bound to plasma proteins. Corifollitropin alfa metabolism: The metabolic fate of corifollitropin alfa highly resembles that of endogenous glycoprotein hormones, which predominantly is comprised of kidney clearance and the urinary excretion of the intact protein in parallel to kidney catabolism. Methylene blue metabolism: Following distribution into tissues, rapidly reduced to leukomethylene blue (leucomethylthioninium chloride). Metabolism to leucomethylene blue may be less efficient in neonates than in older individuals. Corifollitropin alfa is eliminated via Radioactivity labeling showed that the drug was mainly (86%) excreted in the urine. 90% of the radioactivity in serum was identified as [(125)I]corifollitropin alfa, but only 7-15% of the radioactivity in urine was identified as [(125)I]corifollitropin alfa and its dissociation products, the alpha- and beta-subunits (including its CTP part). Elimination of corifollitropin alfa mainly occurs via the kidneys. The elimination rate of this drug may be reduced in patients with renal insufficiency. Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa. Methylene blue is eliminated via Excreted in urine and bile. About 75% of an oral dose excreted in urine, primarily as stabilized colorless leukomethylene blue. The half-life of Corifollitropin alfa is Corifollitropin alfa has a longer half-life compared with FSH and thus requires less frequent dosing. Corifollitropin alfa has an elimination half-life of 70 hours (59-82 hours). The half-life of Methylene blue is 5–6. 5 hours (after IV dose). The clearance of Corifollitropin alfa is 0. 13 L/h (0. 10-0. 18 L/h1). The clearance of Methylene blue is 3. 0 ± 0. 7 L/min. Corifollitropin alfa toxicity includes The most common side effects with Elonva (seen in between 1 and 10 patients in 100) include a headache, nausea, fatigue, pelvic pain and/or discomfort, breast tenderness and ovarian hyperstimulation syndrome (OHSS). This syndrome occurs when the ovaries have a heightened response to therapy, leading to abdominal swelling and pain, nausea and diarrhea. More than one injection of Elonva within one treatment cycle or an excessively high dose of Elonva and/or (rec)FSH can increase the risk of ovarian hyperstimulation syndrome, which may cause swollen or painful ovaries, abdominal bloating, nausea, and a weight gain of up to 3kg. In severe cases, ovarian hyperstimulation syndrome may cause rapid weight gain ranging from 15 to 20 kilograms in 5-10 days. Severe abdominal pain, severe, persistent nausea, and vomiting, decreased urination, and abdominal bloating, as well as other generalized symptoms, may occur. About 1 - 2 % of women undergoing ovarian stimulation develop a severe form of ovarian hyperstimulation syndrome (OHSS). Severe OHSS can be life-threatening. Complications may include: ascites, pulmonary edema, electrolyte disturbances (sodium, potassium, others), thrombosis in large vessels, usually in the lower extremities, renal failure, ovarian torsion, rupture of ovarian cysts. Some of these conditions can lead to hemorrhage, respiratory failure, spontaneous miscarriage or pregnancy termination due to complications, resulting in death. Methylene blue toxicity includes LD50 = 1180 mg/kg ( Rat ). Brand names of Corifollitropin alfa include Elonva. Brand names of Methylene blue include Hyophen, Phosphasal, Provayblue, Proveblue, Urelle, Uribel, Urimar Reformulated Oct 2013, Urin DS, Urogesic Blue Reformulated Apr 2012, Ustell. No synonyms are available for Corifollitropin alfa. No synonyms are available for Methylene blue. Basic Blue 9 C. I. basic blue 9 Chlorure de méthylthioninium Cloruro de metiltioninio Methylene blue Methylenium ceruleum Methylthioninii chloridum Methylthioninium chloride Corifollitropin alfa summary: It is Corifollitropin alfa is a FSH analogue indicated for Controlled Ovarian Stimulation (COS) in combination with a GnRH antagonist for the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) program. Methylene blue summary: It is Methylene blue is an oxidation-reduction agent used for the treatment of pediatric and adult patients with acquired methemoglobinemia. 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.

Corifollitropin alfa

Drug A is Aldesleukin. Drug B is Acalabrutinib. The severity of the interaction is major. The serum concentration of Acalabrutinib can be increased when it is combined with Aldesleukin. 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. Aldesleukin is indicated for treatment of adults with metastatic renal cell carcinoma. 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. 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. 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. 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 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. No absorption information is available for Aldesleukin. Acalabrutinib absorption: The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0. 75 hours. The volume of distribution of Aldesleukin is 0. 18 l/kg. The volume of distribution of Acalabrutinib is The mean steady-state volume of distribution is approximately 34 L. No protein binding information is available for Aldesleukin. 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. No metabolism information is available for Aldesleukin. 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. 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. 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. The half-life of Aldesleukin is 13 min-85 min. 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. No clearance information is available for Aldesleukin. 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. No toxicity information is available for Aldesleukin. Acalabrutinib toxicity includes Data regarding the toxicity of acalabrutinib is not readily available. Brand names of Aldesleukin include Proleukin. Brand names of Acalabrutinib include Calquence. No synonyms are available for Aldesleukin. No synonyms are available for Acalabrutinib. 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. Acalabrutinib summary: It is Acalabrutinib is a Bruton tyrosine kinase inhibitor used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. 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.

Aldesleukin

Drug A is Bimekizumab. Drug B is Anthrax vaccine. The severity of the interaction is major. The therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Bimekizumab. Prescribing information for bimekizumab states that patients undergoing therapy with bimekizumab should not receive live vaccinations. 2 Although the label does not explicitly provide a reasoning, bimekizumab is an inhibitor of IL-17, which has been implicated in vaccine-induced immune responses. The co-administration of bimekizumab with live vaccines may therefore impair the effectiveness of the vaccine in question. 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. 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. 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. Bimekizumab absorption: In healthy volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70. 1%. 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 protein binding information is available for Bimekizumab. Bimekizumab metabolism: As a monoclonal antibody, bimekizumab is likely degraded into smaller peptides and amino acids via catabolic processes. Bimekizumab 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 clearance of Bimekizumab is The median apparent clearance of bimekuzmab in patients with plaque psoriasis was 0. 337 L/day. 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. Brand names of Bimekizumab include No brand names available. No synonyms are available for Bimekizumab. Bimekizumab summary: It is Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment plaque psoriasis. Anthrax vaccine summary: It is Summary not found. Answer: Prescribing information for bimekizumab states that patients undergoing therapy with bimekizumab should not receive live vaccinations. 2 Although the label does not explicitly provide a reasoning, bimekizumab is an inhibitor of IL-17, which has been implicated in vaccine-induced immune responses. The co-administration of bimekizumab with live vaccines may therefore impair the effectiveness of the vaccine in question.

Bimekizumab

Drug A is Bimekizumab. Drug B is Mobocertinib. The severity of the interaction is moderate. The metabolism of Mobocertinib 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 CYP3A5 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. Mobocertinib is indicated for Mobocertinib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. 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. Mobocertinib pharmacodynamics: Mobocertinib is an inhibitor of EGFR that preferentially targets exon 20 insertion mutant variants. It is available as an oral capsule taken with or without food once daily. Mobocertinib can cause a concentration-dependent increase in QTc interval which may lead to life-threatening complications such as Torsades de Pointes. Patients with baseline risk factors for QTc prolongation should consider alternative medications or be monitored carefully throughout therapy. The use of concomitant QTc-prolonging medications should be avoided, as should concomitant inhibitors of CYP3A, as these may increase the concentration of mobocertinib and thus the risk of QTc-prolongation. 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 Mobocertinib is that it The epidermal growth factor receptor (EGFR) is a transmembrane receptor that regulates signaling pathways in the control of cellular proliferation. Mutations in these proteins have been associated with certain types of lung cancer, including non-small cell lung cancer (NSCLC). While the majority of EGFR mutations associated with NSCLC involve the EGFR L858R point mutation or exon 19 deletions (referred to as "classical" EGFR mutations), less common EGFR exon 20 insertion mutations carry a particularly poor prognosis and are associated with resistance to standard targeted EGFR inhibitors. Mobocertinib is an inhibitor of EGFR that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild-type EGFR proteins, exerting a pharmacologic effect on mutant variants at concentrations 1. 5- to 10-fold lower than on wild-type proteins. Bimekizumab absorption: In healthy volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70. 1%. Mobocertinib absorption: The mean absolute bioavailability of mobocertinib is 37% and the median Tmax is approximately 4 hours. Following a single oral dose of 160mg of mobocertinib to fasted patients, the mean Cmax and AUC 0-inf were 45. 8 ng/mL and 862 ng•h/mL, respectively. The volume of distribution of Bimekizumab is In patients with plaque psoriasis, the median volume of distribution at steady-state was 11. 2 L. The volume of distribution of Mobocertinib is The mean apparent volume of distribution of mobocertinib was approximately 3,509 L at steady-state. No protein binding information is available for Bimekizumab. Mobocertinib is Mobocertinib and its metabolites are extensively protein-bound in plasma, although the specific proteins to which they bind have not been elucidated. Following oral administration, mobocertinib is 99. 3% protein-bound, AP32960 is 99. 5% protein-bound, and AP32914 is 98. 6% protein-bound. bound to plasma proteins. Bimekizumab metabolism: As a monoclonal antibody, bimekizumab is likely degraded into smaller peptides and amino acids via catabolic processes. Mobocertinib metabolism: Mobocertinib is metabolized primarily by CYP3A enzymes to two active metabolites, AP32960 and AP32914, which are equipotent to mobocertinib and account for 36% and 4% of its combined molar AUC, respectively. Bimekizumab is eliminated via No route of elimination available. Mobocertinib is eliminated via Following oral administration of mobocertinib, approximately 76% of the administered dose was recovered in the feces (6% as unchanged parent drug) with only 4% recovered in the urine (1% as unchanged parent drug). The metabolite AP32960 comprised 12% and 1% of the recovered dose found in the feces and urine, respectively, while the metabolite AP32914 was below the detection limit in both. 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 Mobocertinib is At steady-state, the mean elimination half-life of mobocertinib and its two active metabolites, AP32960 and AP32914, was 18 hours, 24 hours, and 18 hours, respectively. The clearance of Bimekizumab is The median apparent clearance of bimekuzmab in patients with plaque psoriasis was 0. 337 L/day. The clearance of Mobocertinib is At steady-state, the mean apparent oral clearance of mobocertinib and its two active metabolites, AP32960 and AP32914, was 138 L/hr, 149 L/hr, and 159 L/hr, respectively. 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. Mobocertinib toxicity includes No data are available regarding overdosage with mobocertinib. Symptoms of overdosage are likely to be consistent with mobocertinib's adverse effects and may therefore include significant gastrointestinal symptoms, pain, fatigue, and rash. Brand names of Bimekizumab include No brand names available. Brand names of Mobocertinib include Exkivity. No synonyms are available for Bimekizumab. No synonyms are available for Mobocertinib. Bimekizumab summary: It is Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment plaque psoriasis. Mobocertinib summary: It is Mobocertinib is an oral kinase inhibitor targeted against EGFR and used in the treatment of NSCLC with EGFR exon 20 insertion mutations. 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 CYP3A5 substrates.

Bimekizumab

Drug A is Canakinumab. Drug B is Teprotumumab. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Canakinumab is combined with Teprotumumab. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Canakinumab is indicated for Canakinumab is indicated for the treatment of periodic fever syndromes in specific patient populations. In patients ≥4 years of age, canakinumab is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS). In adult and pediatric patients, canakinumab is also indicated for the treatment of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), and Familial Mediterranean Fever (FMF). Canakinumab is additionally indicated in patients ≥2 years of age for the treatment of active Still's disease, including Adult-Onset Still's Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA). Canakinumab is also indicated for the treatment of gout flares in adult patients in whom standard therapies (e. g. NSAIDs, colchicine) are contraindicated, not tolerated, or ineffective, and in whom repeated courses of corticosteroids are not appropriate. Teprotumumab is indicated for Teprotumumab is indicated for the treatment of thyroid eye disease regardless of disease activity or duration. Canakinumab pharmacodynamics: Canakinumab neutralizes the activity of human IL-1β, which is involved in several inflammatory disorders. Canakinumab has promising clinical safety and pharmacokinetic properties, and demonstrated potential for the treatment of cryopyrin-associated periodic syndromes (CAPS), systemic juvenile idiopathic arthritis (SJIA), and possibly for other complex inflammatory diseases, such as rheumatoid arthritis, COPD disease and ocular diseases. Teprotumumab pharmacodynamics: Teprotumumab inhibits the downstream effects of IGF-1R signaling, namely tissue inflammation and remodeling, which are responsible for the various symptoms of thyroid eye disease. Teprotumumab may cause disease flares in patients with pre-existing inflammatory bowel disease (IBD) - patients experiencing an exacerbation should discontinue therapy with teprotumumab. Significant hyperglycemia has been observed in patients receiving treatment with teprotumumab which may require antihyperglycemic medications. Based on its mechanism of action, it is likely that teprotumumab will cause fetal harm in pregnant woman - for this reason, females of child-bearing age should use effective contraception prior to initiation, during therapy, and for 6 months following the last dose of teprotumumab. The mechanism of action of Canakinumab is that it In inflammatory diseases involving Cryopyrin-Associated Periodic Syndromes (CAPS), interleukin-1 beta (IL-1β) is excessively activated and drives inflammation. The protein cryopyrin controls the activation of IL-1β, and mutations in cryopyrin's gene, NLRP-3, up-regulate IL-1β activation. Canakinumab binds to human IL-1β and neutralizes its inflammatory activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra). The mechanism of action of Teprotumumab is that it Graves’ Disease is an autoimmune syndrome involving the thyroid, orbital connective tissues, and some regions of the skin. One manifestation of Graves’ Disease is thyroid-associated ophthalmopathy, or thyroid eye disease, which is characterized by orbital inflammation, tissue remodeling, and fibrosis. As the disease progresses, patients may develop proptosis, strabismus, corneal ulceration, and optic neuropathy. It has been demonstrated that insulin-like growth factor-1 receptors (IGF-1R) are overexpressed by orbital fibroblasts in patients with thyroid eye disease, in addition to being overexpressed on T-cells and B-cells in these patients. It was found that Graves’ Disease IgG molecules could mimic the principal ligand of IGF-1R, insulin-like growth factor-1 (IGF-1), and their binding of IGF-1R induces the expression of chemokines that play roles in tissue remodeling and inflammation. For these reasons, IGF-1R was sought after as a potential therapeutic target for the treatment of thyroid eye disease. Teprotumumab is a fully human IgG1 monoclonal antibody directed against IGF-1R. It binds to and induces internalization and degradation of these receptors, thus preventing their downstream effects and alleviating symptoms of thyroid eye disease. Canakinumab absorption: The absolute bioavailability of subcutaneously administered canakinumab is estimated to be 66%. Peak serum concentration is 16 ± 3. 5 mcg/mL and occurs approximately 7 days following a single subcutaneous dose of 150mg. Exposure to canakinumab increases proportionately to the administered dose. Teprotumumab absorption: In a population of 40 patients receiving standard dosing in two clinical trials of teprotumumab, utilizing a two-compartment pharmacokinetic model, the AUC and Cmax were estimated to be 138 ± 34 mg•hr/mL and 632 ± 139 mcg/mL, respectively. The volume of distribution of Canakinumab is The steady-state volume of distribution of canakinumab is variable based on weight - it was estimated to be 6. 01 liters in a typical CAPS patient weighing 70 kg, 3. 2 liters in a SJIA patient weighing 33 kg, 6. 34 liters for a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 7. 9 liters in a typical patient with gout flares weighing 93 kg. The volume of distribution of Teprotumumab is Following the standard dosing regimen, the mean central and peripheral volumes of distribution are approximately 3. 26 ± 0. 87 L and 4. 32 ± 0. 67 L, respectively. Canakinumab is Canakinumab binds to plasma IL-1β, but plasma protein binding has not been quantified. bound to plasma proteins. Teprotumumab is Data regarding teprotumumab serum protein binding is unavailable at this time. bound to plasma proteins. Canakinumab metabolism: Canakinumab, like other therapeutic proteins, is likely degraded via non-specific catabolic processes to smaller peptides and amino acids. Teprotumumab metabolism: The metabolism of teprotumumab has not been fully characterized. As a protein, its metabolism is expected to involve proteolysis to smaller proteins and peptides. Canakinumab is eliminated via The route of elimination for canakinumab has not yet been determined. Teprotumumab is eliminated via Data regarding specific route(s) of elimination are unavailable at this time. The half-life of Canakinumab is 26 days. The half-life of Teprotumumab is The half-life of teprotumumab is 20 ± 5 days. The clearance of Canakinumab is The clearance of canakinumab is variable based on weight - it was estimated to be 0. 174 L/day in a typical CAPS patient weighing 70 kg, 0. 11 L/day in an SJIA patient weighing 33 kg, 0. 17 L/day in a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 0. 23 L/day in a typical patient with gout flares of body weight 93 kg. The clearance of Teprotumumab is The estimated mean clearance of teprotumumab is 0. 27 L/day. The inter-compartment clearance is 0. 74 L/day. Canakinumab toxicity includes There are no confirmed cases of overdosage with canakinumab. In the event of an overdose, the patient should be monitored closely and appropriate symptomatic treatment should be administered immediately as clinically indicated. Teprotumumab toxicity includes Toxicity information, including information regarding overdosage, is currently unavailable. Symptoms of teprotumumab overdose are likely to be consistent with its adverse effect profile. Brand names of Canakinumab include Ilaris. Brand names of Teprotumumab include Tepezza. No synonyms are available for Canakinumab. No synonyms are available for Teprotumumab. Canakinumab summary: It is Canakinumab is an interleukin-1β blocker used to treat Periodic Fever Syndromes such as Cryopyrin-Associated Periodic Syndromes (CAPS) and Familial Mediterranean Fever (FMF), and also to treat active Systemic Juvenile Idiopathic Arthritis (SJIA). Teprotumumab summary: It is Teprotumumab is a fully human monoclonal antibody directed against insulin-like growth factor-1 receptor for the treatment of thyroid eye disease. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Canakinumab

Drug A is Acetazolamide. Drug B is Ciprofloxacin. The severity of the interaction is moderate. Acetazolamide may increase the excretion rate of Ciprofloxacin 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. Acetazolamide is indicated for adjunctive treatment of: edema due to congestive heart failure; drug-induced edema; centrencephalic epilepsies; chronic simple (open-angle) glaucoma. Ciprofloxacin is indicated for Ciprofloxacin is only indicated in infections caused by susceptible bacteria. Ciprofloxacin immediate release tablets, oral suspensions, and intravenous injections are indicated for the treatment of skin and skin structure infections, bone and joint infections, complicated intra-abdominal infections, nosocomial pneumonia, febrile neutropenia, adults who have inhaled anthrax, plague, chronic bacterial prostatitis, lower respiratory tract infections including acute exacerbations of chronic bronchitis, urinary tract infections, complicated urinary tract infections in pediatrics, complicated pyelonephritis in pediatrics, and acute sinusitis. A ciprofloxacin otic solution and otic suspension with hydrocortisone are indicated for acute otitis externa. Ciprofloxacin suspension with dexamethasone is indicated for acute otitis media in pediatric patients with tympanostomy tubes or acute otitis externa. A ciprofloxacin intratympanic injection is indicated for pediatric patients with bilateral otitis media with effusion who are having tympanostomy tubes placed or pediatric patients 6 months or older with acute otitis externa. A ciprofloxacin eye drop is indicated for bacterial corneal ulcers and conjunctivitis. A ciprofloxacin eye ointment is indicated for bacterial conjunctivitis. A ciprofloxacin extended release tablet is indicated for uncomplicated urinary tract infections, complicated urinary tract infections, and acute uncomplicated pyelonephritis. 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. Ciprofloxacin pharmacodynamics: Ciprofloxacin is a second generation fluoroquinolone that is active against many Gram negative and Gram positive bacteria. It produces its action through inhibition of bacterial DNA gyrase and topoisomerase IV. Ciprofloxacin binds to bacterial DNA gyrase with 100 times the affinity of mammalian DNA gyrase. There is no cross resistance between fluoroquinolones and other classes of antibiotics, so it may be of clinical value when other antibiotics are no longer effective. Ciprofloxain and its derivatives are also being investigated for its action against malaria, cancers, and AIDS. 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 Ciprofloxacin is that it Ciprofloxacin acts on bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Ciprofloxacin's targeting of the alpha subunits of DNA gyrase prevents it from supercoiling the bacterial DNA which prevents DNA replication. No absorption information is available for Acetazolamide. Ciprofloxacin absorption: A 250mg oral dose of ciprofloxacin reaches an average maximum concentration of 0. 94mg/L in 0. 81 hours with an average area under the curve of 1. 013L/h*kg. The FDA reports an oral bioavailability of 70-80% while other studies report it to be approximately 60%. An early review of ciprofloxacin reported an oral bioavailability of 64-85% but recommends 70% for all practical uses. No volume of distribution information is available for Acetazolamide. The volume of distribution of Ciprofloxacin is Cirpofloxacin follws a 3 compartment distribution model with a central compartment volume of 0. 161L/kg and a total volume of distribution of 2. 00-3. 04L/kg. Acetazolamide is 98% bound to plasma proteins. Ciprofloxacin is 20-40%. bound to plasma proteins. No metabolism information is available for Acetazolamide. Ciprofloxacin metabolism: Ciprofloxacin is primarily metabolized by CYP1A2. The primary metabolites oxociprofloxacin and sulociprofloxacin make up 3-8% of the total dose each. Ciprofloxacin is also converted to the minor metabolites desethylene ciprofloxacin and formylciprofloxacin. These 4 metabolites account for 15% of a total oral dose. There is a lack of available data on the enzymes and types of reactions involved in forming these metabolites. Acetazolamide is eliminated via No route of elimination available. Ciprofloxacin is eliminated via 27% of an oral dose was recovered unmetabolized in urine compared to 46% of an intravenous dose. Collection of radiolabelled ciprofloxacin resulted in 45% recovery in urine and 62% recovery in feces. The half-life of Acetazolamide is 3 to 9 hours. The half-life of Ciprofloxacin is The average half life following a 250mg oral dose was 4. 71 hours and 3. 65 hours following a 100mg intravenous dose. Generally the half life is reported as 4 hours. No clearance information is available for Acetazolamide. The clearance of Ciprofloxacin is The average renal clearance after a 250mg oral dose is 5. 08mL/min*kg. Following a 100mg intravenous dose, the average total clearance is 9. 62mL/min*kg, average renal clearance is 4. 42mL/min*kg, and average non renal clearance is 5. 21mL/min*kg. No toxicity information is available for Acetazolamide. Ciprofloxacin toxicity includes Patients experiencing an overdose may present with nausea, vomiting, abdominal pain, crystalluria, nephrotoxicity, and oliguria. Ciprofloxacin overdose typically leads to acute renal failure. An overdose may progress over the next 6 days with rising serum creatinine and BUN, as well as anuria. Patients may require prednisone therapy, urgent hemodialysis, or supportive therapy. Depending on the degree of overdose, patients may recover normal kidney function or progress to chronic kidney failure. The oral LD50 in rats is >2000mg/kg. Ciprofloxacin for intratympanic injection or otic use has low systemic absorption and so it unlikely to be a risk in pregnancy or lactation. There is generally no harm to the fetus in animal studies, however high doses may lead to gastrointestinal disturbances in the mother which may increase the incidence of abortion. In human studies there was no increase in fetal malformations above background rates. The risk and benefit of ciprofloxacin should be weighed in pregnancy and breast feeding. 2/8 in vitro tests and 0/3 in vivo tests of mutagenicity of ciprofloxacin have yielded a positive result. Oral doses of 200 and 300 times the maximum recommended clinical dose in rats and mice have shown no carcinogenicity or tumorigenicity. Oral doses above the maximum recommended clinical dose have shown no effects on fertility in rats. Brand names of Acetazolamide include No brand names available. Brand names of Ciprofloxacin include Cetraxal, Ciloxan, Cipro, Cipro HC, Ciprodex, Ciprofloxacin, Otiprio, Otixal, Otovel, Proquin. No synonyms are available for Acetazolamide. Acetazolamida Acétazolamide Acetazolamide Acetazolamidum No synonyms are available for Ciprofloxacin. Ciprofloxacine Ciprofloxacino Ciprofloxacinum 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. Ciprofloxacin summary: It is Ciprofloxacin is a second generation fluoroquinolone used to treat various susceptible bacterial infections. 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.

Acetazolamide

Drug A is Acenocoumarol. Drug B is Selumetinib. The severity of the interaction is moderate. The metabolism of Selumetinib can be decreased when combined with Acenocoumarol. Substrates of the CYP2C19 enzyme compete for metabolism by this enzyme, causing increased exposure to either CYP2C19 substrate drug. 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. Selumetinib is indicated for Selumetinib is indicated for the treatment of neurofibromatosis type 1 (NF1) in patients two years and older who have symptomatic, inoperable plexiform neurofibromas (PN). 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. Selumetinib pharmacodynamics: Selumetinib is a non-ATP-competitive mitogen-activated protein kinase 1 and 2 (MEK1 and MEK2) inhibitor. By selectively targeting MEK1 and MEK2, selumetinib is able to inhibit oncogenic downstream effects of the Raf-MEK-ERK signaling pathway, which is often overactive in certain types of cancer. Indeed, a study investigating the effects of selumetinib in children with NF-1 found that treatment with the anti-neoplastic resulted in reduced tumor size. Decreases in tumor-associated pain and improvements in overall function were also subjectively reported. Selumetinib has minimal off-target activity, contributing to its impressive safety profile. 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 Selumetinib is that it The Ras-Raf-MEK-ERK signaling cascade is known to be activated in several types of cancer, and regulates the transcription of proteins involved in apoptosis. In addition, studies have shown that mutations of the Raf component of the pathway can contribute to chemotherapy drug resistance. Ras as well as several kinases and phosphatases are responsible for regulating the Raf-MEK-ERK pathway. Often in cancers, Ras (a G-protein coupled receptor) is deregulated, allowing downstream signalling to proceed unchecked. Through several complex steps, Raf phosphorylates and activates MEK, which then phosphorylates and activates ERK. ERK is then able to exert its effects on several downstream targets. As such, therapies inhibiting upstream components of this pathway have become attractive targets for cancer treatment. Selumetinib exerts its effects by selectively inhibiting MEK1 and MEK2 which can effectively blunt the pleiotropic effects of the Ras-Raf-MEK-ERK cascade. By inhibiting this oncogenic pathway, selumetinib reduces cell proliferation, and promotes pro-apoptotic signal transduction. Acenocoumarol absorption: Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration. Selumetinib absorption: Based on several studies investigating selumetinib at various doses in both pediatric and adult populations, the Tmax generally ranges between 1- 1. 5 hours. In healthy adults, the mean absolute oral bioavailability was reported to be 62%. Selumetinib should be administered on an empty stomach since food significantly decreases serum concentrations of the drug. 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 Selumetinib is The mean apparent volume of distribution of selumetinib at steady state in pediatric patients ranged from 78 L to 171 L. A study in healthy adult males found a mean apparent volume of distribution of 146 L. Another study observing the pharmacokinetic effects of various selumetinib doses and regimens in select Japanese patients found that the apparent volume of distribution values at steady-state ranged from 73. 2 - 148. 1 L. Acenocoumarol is 98. 7% protein bound, mainly to albumin bound to plasma proteins. Selumetinib is Separate studies investigating selumetinib protein binding found that 96% of selumetinib was bound to serum albumin, while <35% was bound to ɑ-1 acid glycoprotein. Overall, approximately 98. 4% of selumetinib is plasma protein bound. 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. Selumetinib metabolism: Selumetinib is heavily metabolized in the liver and the proposed metabolic pathway is as follows: Hydrolysis of selumetinib’s amide functional group produces M15 (AZ13326637), which contains a carboxylic acid. Elimination of the ethanediol moiety from the parent compound results in the formation of the primary amide M14 (AZ12791138) metabolite. Amide hydrolysis transforms M14 into M15, glucuronidation and further oxidation of M14 leads to M2, M6 and M1, and N-demethylation of M14 produces M12. The amide glucuronide (M2) is thought to be the major circulating metabolite. Demethylation of selumetinib produces the pharmacologically active M8 (AZ12442942), and further oxidation of M8 leads to M11. Glucuronidation of M8 produces M3 or M5, and elimination of the ethanediol moiety from M8 results in a primary amide, producing M12. Although the N-demethylated metabolite (M8) accounts for <10% of the circulating metabolites, it is responsible for approximately 21-35% of any observed pharmacological activity. Ribose conjugation transforms M12 into M9, while oxidation of M12 leads to M10 and M13 metabolites. Glucuronidation of M10 produces M1. Direct glucuronidation of selumetinib produces M4 or M7, which can both eventually transform into M3 and M5 metabolites. Acenocoumarol is eliminated via Mostly via the kidney as metabolites. Selumetinib is eliminated via Approximately 59% of selumetinib is eliminated in the feces, while 33% is eliminated in the urine. The half-life of Acenocoumarol is 8 to 11 hours. The half-life of Selumetinib is Selumetinib is characterized by a short half-life. The elimination half-life associated with a dose of 25 mg/m in pediatric patients is 6. 2 hours. In a study observing the pharmacokinetic effects of various selumetinib regimens in select Japanese patients, the half-life ranged from 9. 2- 10. 6 hours. In other studies where selumetinib 75 mg is administered twice daily, the half-life is reported to be approximately 13 hours. No clearance information is available for Acenocoumarol. The clearance of Selumetinib is The clearance of selumetinib in pediatric patients is 8. 8 L/hr. A study in healthy adult males found a clearance value of 15. 7 L/hr. Another study observing the pharmacokinetic effects of various selumetinib doses and regimens in select Japanese patients found clearance values that ranged from 9. 2 - 15. 9 L/hr. 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. Selumetinib toxicity includes Toxicity information regarding selumetinib is not readily available. Patients experiencing an overdose are at an increased risk of adverse effects such as cardiomyopathy, ocular toxicity, and diarrhea. It is generally thought that since selumetinib is extensively protein-bound, dialysis is unlikely to be helpful in situations of overdose. Brand names of Acenocoumarol include No brand names available. Brand names of Selumetinib include Koselugo. No synonyms are available for Acenocoumarol. Acénocoumarol Acenocoumarol Acenocoumarolum Acenocumarol Acenocumarolo Acenokumarin Nicoumalone Nicumalon Nitrovarfarian Nitrowarfarin No synonyms are available for Selumetinib. 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. Selumetinib summary: It is Selumetinib is a MEK 1/2 inhibitor used in pediatric patients to treat neurofibromatosis type 1 (NF1) accompanied by symptomatic, inoperable plexiform neurofibromas (PN). Answer: Substrates of the CYP2C19 enzyme compete for metabolism by this enzyme, causing increased exposure to either CYP2C19 substrate drug.

Acenocoumarol

Drug A is Nivolumab. Drug B is Fremanezumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Nivolumab is combined with Fremanezumab. 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. Nivolumab is indicated for Nivolumab is indicated to treat unresectable or metastatic melanoma, melanoma as adjuvant treatment, resectable or metastatic non-small cell lung cancer, small cell lung cancer, advanced renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer, hepatocellular carcinoma, and esophageal cancer. The indication for classical Hodgkin lymphoma, microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer, and hepatocellular carcinoma were approved under accelerated approval based on the overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Nivolumab is also approved for the treatment of HER2-negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma when used in combination with a fluoropyrimidine- and platinum-containing chemotherapy regimen. In combination with relatlimab, nivolumab is indicated for the treatment of patients ≥12 years old with unresectable or metastatic melanoma. Fremanezumab is indicated for Fremanezumab is indicated for the preventative treatment of migraine in adults. Nivolumab pharmacodynamics: Nivolumab blocks PD-1 inhibitory signalling to T-cells. It has a long duration of action as it is administered every 2-4 weeks. Patients should be counselled regarding the risk of immune-mediated adverse effects, infusion-related adverse effects, complications of allogenic hematopoietic stem cell transplants, embryo-fetal toxicity. Fremanezumab pharmacodynamics: Fremanezumab is a subcutaneous injection that targets the calcitonin gene-related peptide (CGRP) ligand, preventing its binding to the CGRP receptor. It possesses a long duration of action requiring only monthly or quarterly administration and appears well-tolerated in clinical trials. The mechanism of action of Nivolumab is that it The ligands PD-L1 and PD-L2 bind to the PD-1 receptor on T-cells, inhibiting the action of these cells. Tumor cells express PD-L1 and PD-L2. Nivolumab binds to PD-1, preventing PD-L1 and PD-L2 from inhibiting the action of T-cells, restoring a patient's tumor-specific T-cell response. The mechanism of action of Fremanezumab is that it Studies dating back to 1985 have demonstrated that CGRP levels increase during acute migraine attacks in migraine-suffering patients but normalize after administration of antimigraine therapy such as sumatriptan. Moreover, research has shown that intravenous administration of CGRP can induce migraine-like attacks in migraine-suffering patients. For these reasons, and despite the fact that their role in migraine headaches has not been entirely elucidated, CGRP and its receptors have become desirable targets for antimigraine therapies. Fremanezumab is a humanized monoclonal antibody directed against endogenous CGRP - it interferes with the activity of CGRP, preventing its downstream effects and ultimately mitigating the development of migraine headaches. Nivolumab absorption: Pharmacokinetic studies have suggested that nivolumab presents linear pharmacokinetics with a dose-proportional increase in peak concentration and AUC. The time to peak plasma concentration ranges between 1-4 hours. The absorption pharmacokinetic properties respective to the administration of a dose of 10 mg/kg are reported to be Cmax, Tmax and AUC of 242 µg/kg, 2. 99 hours and 68100 µg*h/mL respectively. Fremanezumab absorption: Geometric mean ratios (GMRs) for Cmax for Japanese and Caucasian study subjects were 0. 91, 1. 04, and 1. 14 for 225 mg, 675 mg, and 900 mg doses of fremanezumab. GMRs for AUC (0-inf) were 0. 96, 1. 09, and 0. 98, respectively. Mean Tmax in a range of 5 to 11 days were similar across doses for both ethnicities as well. The volume of distribution of Nivolumab is The volume of distribution at steady state when a dose of 10 mg/kg of nivolumab is administered is reported to be 91. 1 mL/kg. At doses ranging from 0. 1 to 20 mg/kg the volume of distribution is reported to be 8L. The volume of distribution of Fremanezumab is Fremanezumab has an apparent volume of distribution of approximately 6 liters which indicates very little distribution into tissue. Nivolumab is There is no information regarding the plasma protein binding of nivolumab. bound to plasma proteins. Fremanezumab is Data regarding protein binding of fremanezumab are not readily available. bound to plasma proteins. Nivolumab metabolism: There have not been formal studies regarding the specific metabolism of nivolumab but as a human monoclonal antibody, it has been suggested to be degraded to small peptides and individual amino acids. Fremanezumab metabolism: Like other monoclonal antibodies, fremanezumab is expected to undergo enzymatic proteolysis into smaller peptides and amino acids. Nivolumab is eliminated via There have not been studies regarding the specific route of elimination of nivolumab. Fremanezumab is eliminated via Monoclonal antibody agents like fremanezumab are generally not eliminated via hepatic, renal, or biliary routes. The half-life of Nivolumab is The serum half life of nivolumab is approximately 20 days with an elimination half life of 26. 7 days. The half-life of Fremanezumab is The mean half-life recorded for fremanezumab was similar across doses for Japanese and Caucasian study subjects and was estimated to be approximately 31-39 days. The clearance of Nivolumab is The estimated clearance rate of nivolumab is 9. 4 mL/h. The clearance rate seems to be increased according to body weight. The clearance of Fremanezumab is The apparent clearance of fremanezumab is 0. 141 L/day. Nivolumab toxicity includes Data regarding overdoses of nivolumab are not readily available. Common adverse effects include Rash, pruritus, cough, upper respiratory tract infection, and peripheral edema. Fremanezumab toxicity includes Information regarding overdose of fremanezumab is not readily available. The most common adverse events that led to discontinuation of fremanezumab therapy were injection site reactions including erythema, induration, and pain. Brand names of Nivolumab include Opdivo, Opdualag. Brand names of Fremanezumab include Ajovy. No synonyms are available for Nivolumab. No synonyms are available for Fremanezumab. Nivolumab summary: It is Nivolumab is a PD-1 blocking antibody used to treat melanoma, non small-cell lung cancer, renal cell cancer, head and neck cancer, and Hodgkin lymphoma. Fremanezumab summary: It is Fremanezumab is a humanized monoclonal antibody directed against human calcitonin-gene related peptide to prevent migraines. 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.

Nivolumab

Drug A is Ravulizumab. Drug B is Gemtuzumab ozogamicin. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Ravulizumab. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Ravulizumab is indicated for Ravulizumab is indicated for the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH). It is also indicated for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). However, the FDA advises against the use of ravulizumab for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). Ravulizumab is also indicated for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive. It is indicated for the treatment of adult patients with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive. The European Commission approved ravulizumab for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) in adults and children with a body weight of 10 kg or more with the following conditions: hemolysis with clinical symptoms indicative of high disease activity or clinically stable after having been treated with eculizumab for at least the past six months. Ravulizumab is also indicated for the treatment of hemolytic uremic syndrome (aHUS) in patients with a body weight of 10 kg or more who are either complement inhibitor treatment-naïve or have received eculizumab for at least 3 months and have evidence of response to eculizumab. Gemtuzumab ozogamicin is indicated for Indicated for the treatment of patients with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. Indicated for the treatment of patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment (refractory). Ravulizumab pharmacodynamics: Ravulizumab is a potent long-acting complement inhibitor of C5, which is a key complement protein involved in inflammatory and thrombotic pathways. It has a long duration of action and fast onset of action. In a clinical study of adult and pediatric patients with paroxysmal nocturnal hemoglobinuria, completion inhibition of free C5 - determined as the serum concentration of less than 0. 5 mcg/mL - was observed by the end of the first ravulizumab infusion: this effect was sustained throughout the entire 26-week treatment period. In patients with atypical hemolytic uremic syndrome, inhibition of C5 was observed in 93% of the patients in the study. C5 inhibition by ravulizumab is exposure-dependent. Gemtuzumab ozogamicin pharmacodynamics: Used for the treatment of acute myeloid leukemia (AML), mylotarg binds to the CD33 antigen, which is expressed on the surface of leukemic cells in more than 80% of patients with AML. The CD33 antigen is not expressed on pluripotent hematopoietic stem cells or nonhematopoietic cells. This gives mylotarg the selectivity needed to target leukemic cells. The mechanism of action of Ravulizumab is that it Complement system activation plays an important role in innate and acquired immunity. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by hemolytic anemia, bone marrow failure, and thrombosis. It is caused by a genetic mutation, leading to complement-mediated hemolysis and deficiencies in glycosylphosphatidylinositol (GPI)-linked proteins such as those involved in fibrinolysis. Atypical hemolytic uraemic syndrome (aHUS) is a type of thrombotic microangiopathy also caused by complement dysregulation. It is associated with thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage. Myasthenia gravis, an autoimmune neuromuscular disease, also involves the immune system aberrantly attacking the muscles, causing progressive muscle damage. Ravulizumab inhibits the terminal complement pathway by binding to C5 with high affinity: this inhibits the cleavage of C5 to C5a, which is a pro-inflammatory and pro-thrombotic anaphylatoxin, and C5b, an initiating subunit of the terminal complement complex (C5b-9), which promotes cell lysis. Since the generation of C5b is blocked, the formation of C5b-9 is also inhibited by ravulizumab. Ravulizumab inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. By blocking the complement system, ravulizumab ameliorates the extent of inflammatory and immune responses that play a role in the pathophysiology of myasthenia gravis. The mechanism of action of Gemtuzumab ozogamicin is that it Mylotarg is directed against the CD33 antigen expressed by hematopoietic cells. Binding of the anti-CD33 antibody portion of Mylotarg with the CD33 antigen results in the formation of a complex that is internalized. Upon internalization, the calicheamicin derivative is released inside the lysosomes of the myeloid cell. The released calicheamicin derivative binds to DNA in the minor groove resulting in site-specific DNA double strand breaks via formation of a p-benzene diradical. Eventually, cell death is induced. Ravulizumab absorption: In children with paroxysmal nocturnal hemoglobinuria who are complement inhibitor-naïve, the mean Cmax was 733 mcg/mL following the loading dose and 1490 mcg/mL following the maintenance dose. In children who were previously treated with eculizumab, the mean Cmax was 885 mcg/mL following the loading dose and 1705 mcg/mL following the maintenance dose. In adults with paroxysmal nocturnal hemoglobinuria who are complement inhibitor-naïve, the mean Cmax was 771 mcg/mL following the loading dose and 1379 mcg/mL following the maintenance dose. In adults who were previously treated with eculizumab, the mean Cmax was 843 mcg/mL following the loading dose and 1386 mcg/mL following the maintenance dose. In children with atypical hemolytic uremic syndrome and a body weight of less than 20 kg, the mean Cmax was 656 mcg/mL following the loading dose and 1467 mcg/mL following the maintenance dose. In children with a body weight ranging from 20 to 40 kg, the mean Cmax was 600 mcg/mL following the loading dose and 1863 mcg/mL following the maintenance dose. In adults with a body weight greater than 40 kg, the mean Cmax was 754 mcg/mL following the loading dose and 1458 mcg/mL following the maintenance dose. Tmax is expected at the end of infusion (EOI) or soon after EOI. Therapeutic steady-state drug concentrations are reached after the first dose. Gemtuzumab ozogamicin absorption: In pediatric patients receiving a dose level of 9mg/m^2, the peak plasma concentration (Cmax) was approximately 3. 47±1. 04 mg/L with the AUC of 136 ±107 mg * h/L. The volume of distribution of Ravulizumab is The mean (%CV) volume of distribution at steady state was 5. 30 (17. 9) L in patients with paroxysmal nocturnal hemoglobinuria and 5. 22 (35. 4) L in patients with atypical hemolytic uremic syndrome. The volume of distribution of Gemtuzumab ozogamicin is The volume of distribution at steady state (Vss) was approximately 6. 5 ± 5. 5 L in pediatric patients receiving a dose level of 9mg/m^2. Ravulizumab is There is no information on the protein binding of ravulizumab. bound to plasma proteins. No protein binding information is available for Gemtuzumab ozogamicin. Ravulizumab metabolism: Ravulizumab is expected to be metabolized in the same manner as any endogenous immunoglobulin gamma monoclonal antibody: it undergoes degradation into small peptides and amino acids via catabolic pathways. Ravulizumab contains only natural occurring amino acids and has no known active metabolites. Gemtuzumab ozogamicin metabolism: Metabolic studies indicate hydrolytic release of the calicheamicin derivative from gemtuzumab ozogamicin. The drug is most likely removed by opsonization via the reticuloendothelial system. Ravulizumab is eliminated via There is no information on the route of elimination of ravulizumab. Gemtuzumab ozogamicin is eliminated via No route of elimination available. The half-life of Ravulizumab is The mean (%CV) terminal elimination half-life of ravulizumab is 49. 6 (18. 3) days in patients with paroxysmal nocturnal hemoglobinuria and 51. 8 (31. 3) days in patients with atypical hemolytic uremic syndrome. The half-life of Gemtuzumab ozogamicin is In pediatric patients receiving a dose level of 9mg/m^2, the half life was approximately 64±44 h after the first dose. The clearance of Ravulizumab is The mean (%CV) clearance of ravulizumab is 0. 08 (28. 1) L/day in patients with paroxysmal nocturnal hemoglobinuria and 0. 08 (53. 3) L/day in patients with atypical hemolytic uremic syndrome. The clearance of Gemtuzumab ozogamicin is The mean clearance rate was approximately 0. 12±0. 15 L/h/m^2 in pediatric patients receiving a dose level of 9mg/m^2. Ravulizumab toxicity includes There is no information on the LD 50 value of ravulizumab. No case of ravulizumab overdose has been reported to date. Patients who experience overdose should have immediate interruption of their infusion and be closely monitored. Gemtuzumab ozogamicin toxicity includes The most frequently reported toxicities are myelosuppression and hepatic veno-occlusive disorder. Brand names of Ravulizumab include Ultomiris. Brand names of Gemtuzumab ozogamicin include Mylotarg. No synonyms are available for Ravulizumab. No synonyms are available for Gemtuzumab ozogamicin. Ravulizumab summary: It is Ravulizumab is a monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and myasthenia gravis. Gemtuzumab ozogamicin summary: It is Gemtuzumab ozogamicin is a monoclonal anti-CD33 antibody used to treat CD33-positive acute myeloid 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.

Ravulizumab

Drug A is Bupropion. Drug B is Tafenoquine. The severity of the interaction is major. The metabolism of Tafenoquine can be decreased when combined with Bupropion. 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. Bupropion is indicated for Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e. g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. Tafenoquine is indicated for Tafenoquine is used for the treatment and prevention of relapse of Vivax malaria in patients 16 years and older. Tafenoquine is not indicated to treat acute vivax malaria. Malaria is a disease that remains to occur in many tropical countries. Vivax malaria, caused by Plasmodium vivax, is known to be less virulent and seldom causes death. However, it causes a substantive illness-related burden in endemic areas and it is known to present dormant forms in the hepatocytes named hypnozoites which can remain dormant for weeks or even months. This dormant form produces ongoing relapses. Bupropion pharmacodynamics: Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1. 3 mmHg. Tafenoquine pharmacodynamics: In vitro studies have shown that tafenoquine presents an average 50% inhibitory concentration of 0. 436 mcg against blood stages of seven strains of P. falciparum. In chloroquine-resistant P. falciparum strains the IC50 of tafenoquine was greater when compared with primaquine and it ranged from 0. 5 to 33. 1 mcg. In studies evaluating the transmission-blocking activity of tafenoquine against the sporogonic stage of P. vivax, it was showed a reduced transmission at doses higher than 25 mg/kg. In clinical trials, it was reported a tafenoquine-induced relapse prevention of 91. 9% in cases of vivax malaria when pretreated with chloroquine. In prophylactic studies, tafenoquine showed an efficacy range from 84 to 87% against falciparum malaria and 99. 1% against vivax malaria. The mechanism of action of Bupropion is that it Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. The mechanism of action of Tafenoquine is that it The mechanism of action of tafenoquine is not well established but studies have reported a longer and more effective action when compared to primaquine. The active moiety of tafenoquine, 5,6 ortho quinone tafenoquine, seems to be redox cycled by P. falciparum which are upregulated in gametocytes and liver stages. Once inside, the oxidated metabolite produces hydrogen peroxide and hydroxyl radicals. It is thought that these radicals produce leads to the parasite death. On the other hand, tafenoquine inhibits heme polymerase in blood stage of parasites which explains the activity against blood stages of parasites. Bupropion absorption: Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i. e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1. 5 and 7 times that of bupropion, respectively. Tafenoquine absorption: The first-in-human pharmacokinetic study showed a tmax of 13. 8 hours and this study suggested that the prolonged absorption from the gut can be due to absorption in the distal gastrointestinal tract combined with a slow clearance. The AUC and Cmax demonstrated an intersubject variability. The bioavailability of tafenoquine is increased in the presence of a high-fat meal by modifying the amount of drug absorbed rather than the rate of absorption. Once absorbed, the concentration of tafenoquine in the whole body is two-fold higher than the corresponding concentration in plasma and it seems to be highly distributed in the liver showing an AUC of approximately 80 times more than what is found in the plasma. No volume of distribution information is available for Bupropion. The volume of distribution of Tafenoquine is Tafenoquine presents a high volume of distribution of approximately 2 560 L. Bupropion is In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. bound to plasma proteins. Tafenoquine is The plasma protein binding of tafenoquine in humans is very high and it represents about 99. 5%. bound to plasma proteins. Bupropion metabolism: Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. Tafenoquine metabolism: The activation of tafenoquine needs the activity of CYP 2D6 liver microsomal enzyme. This activation step produces the metabolite 5,6 ortho quinone tafenoquine. This metabolite is internalized by the parasite and reduced to radicals by ferredoxin-NADP+ reductase and diflavin reductase enzymes. In the human, tafenoquine is metabolized by several metabolic pathways including O-demethylation, N-dealkylation, N-oxidation and oxidative deamination as well as C-hydroxylation of the 8-aminoalkylamino side chain. Bupropion is eliminated via Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0. 5%, a finding consistent with the extensive metabolism of bupropion. Tafenoquine is eliminated via After degradation by different metabolic pathways, tafenoquine is slowly excreted from the body primarily in the feces and renal elimination of the unchanged form is very low. The half-life of Bupropion is 24 hours. The half-life of Tafenoquine is Tafenoquine presents a long half-life of approximately 14 days. No clearance information is available for Bupropion. The clearance of Tafenoquine is Tafenoquine presents a low clearance of approximately 6 L/h. Bupropion toxicity includes Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. Tafenoquine toxicity includes Tafenoquine can cause hemolysis in people with glucose-6-phosphate dehydrogenase deficiency. In preclinical studies, renal cell adenomas and carcinomas are increased in male rats with an overdose administration. However, this drug does not seem to be carcinogenic in humans and it was shown to lack mutagenic potential. In fertility studies, tafenoquine resulted in a reduced number of viable fetuses, implantation sites and corpora lutea. Brand names of Bupropion include Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban. Brand names of Tafenoquine include Arakoda, Krintafel. No synonyms are available for Bupropion. No synonyms are available for Tafenoquine. Bupropion summary: It is Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. Tafenoquine summary: It is Tafenoquine is an antiparasitic agent used for the treatment and prevention of relapse of Vivax malaria. 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.

Bupropion

Drug A is Ofatumumab. Drug B is Trastuzumab. The severity of the interaction is moderate. The risk or severity of neutropenia can be increased when Trastuzumab is combined with Ofatumumab. While trastuzumab treatment itself can cause neutropenia, its co-administration with other immunosuppressive agents has been shown to result in synergistic neutropenic effects. In randomized controlled clinical trials, patients receiving trastuzumab in combination with myelosuppressive chemotherapy had higher rates of moderate to severe neutropenia and febrile neutropenia compared to those receiving chemotherapy alone. The pathophysiologic basis for this exacerbation of neutropenia has not been determined. 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. Trastuzumab is indicated for the adjuvant treatment of HER2-overexpressing breast cancer, trastuzumab is indicated in several clinical settings: as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a treatment regimen with docetaxel and carboplatin; or as monotherapy following multi-modality anthracycline-based therapy. Trastuzumab is indicated as a first-line treatment, in combination with paclitaxel, for metastatic HER2-overexpressing breast cancer, and as monotherapy in patients who have previously received one or more chemotherapy regimens in the metastatic setting. In Europe, trastuzumab can also be used in combination with paclitaxel or docetaxel for the treatment of metastatic HER2-positive breast cancer in adult patients and with an aromatase inhibitor in postmenopausal patients. For HER2-positive early breast cancer, the EMA approved trastuzumab as monotherapy following surgery, chemotherapy (neoadjuvant or adjuvant), and radiation or following adjuvant chemotherapy with doxorubicin and cyclophosphamide in combination with paclitaxel or docetaxel. It can also be used in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin or with neoadjuvant chemotherapy followed by adjuvant trastuzumab therapy for locally advanced (including inflammatory) disease or tumors > 2 cm in diameter. Trastuzumab is also indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease by the FDA and EMA. Trastuzumab is indicated for subcutaneous administration - in combination with either hyaluronidase or both hyaluronidase and pertuzumab - for the treatment of adults with HER2-positive breast cancers. 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). Trastuzumab pharmacodynamics: Trastuzumab exerts an antitumour activity and is used in the treatment of HER2-positive breast cancer. HER2 protein overexpression is observed in 20%-30% of primary breast cancers thus HER2 presents as a useful therapeutic target for the treatment of breast cancers. Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. It works as a mediator of antibody-dependent cellular cytotoxicity, where it binds as an antibody to cells over-expressing HER2, leading to preferential cell death. Trastuzumab was also shown to inhibit angiogenesis of tumor cells in vivo. Higher doses and longer dosing intervals show no significant benefit over standard dose schedules. In patients with HER2 positive solid tumours, trastuzumab did not exert any clinically significant QTc interval duration. 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 Trastuzumab is that it Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against the HER-2 receptor, a member of the epidermal growth factor receptors which is a photo-oncogene. Over-expressed in breast tumour cells, HER-2 overamplifies the signal provided by other receptors of the HER family by forming heterodimers. The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. It is activated by the formation of homodimers or heterodimers with other EGFR proteins, leading to dimerization and autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains. Further downstream molecular signaling cascades are activated, such as the Ras/Raf/mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways that promote cell growth and survival and cell cycle progression. Due to upregulation of HER-2 in tumour cells, hyperactivation of these signaling pathways and abnormal cell proliferation is observed. Trastuzumab binds to the extracellular ligand-binding domain and blocks the cleavage of the extracellular domain of HER-2 to induce its antibody-induced receptor downmodulation, and subsequently inhibits HER-2-mediated intracellular signaling cascades. Inhibition of MAPK and PI3K/Akt pathways lead to an increase in cell cycle arrest, and the suppression of cell growth and proliferation. Trastuzumab also mediates the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) by attracting the immune cells, such as natural killer (NK) cells, to tumor sites that overexpress HER-2. While the drug alone has a minimal potential to induce complement-dependent cytotoxicity (CDC), one study demonstrated increased therapeutic effectiveness and a synergistic effect on uterine serous carcinoma cells in vitro when used in combination with pertuzumab, which also has minor effects on CDC alone. This study showed that only the combination of both cell-bound antibodies would be sufficient to bind and activate the complement component 1q (C1q) required to initiate the complement cascade reaction. Intrinsic trastuzumab resistance has been noted for some patients with HER-2 positive breast cancer. Mechanisms involving trastuzumab resistance include deficiency of phosphatase and tensin homologue and activation of phosphoinositide 3-kinase, and the overexpression of other surface receptors, such as insulin-like growth factor. 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. Trastuzumab absorption: Peak and trough plasma concentrations at steady state (between weeks 16 and 32) were approximately 123 and 79 mcg/mL, respectively. At the highest weekly dose studied (500 mg), mean peak serum concentration was 377 mcg/mL. 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. No volume of distribution information is available for Trastuzumab. Ofatumumab is There is limited information on the serum protein binding profile of ofatumumab. bound to plasma proteins. No protein binding information is available for Trastuzumab. 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. Trastuzumab metabolism: After it binds to HER2, trastuzumab is metabolized intracellularly into smaller peptides and amino acids. 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. Trastuzumab is eliminated via Following metabolism, the complex elimination of trastuzumab in humans is mediated by epithelial cells in a dose-dependent (nonlinear) fashion. The renal excretion of trastuzumab is very low. 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 Trastuzumab is The terminal half-life is approximately 28 days, but may decrease with lower doses - at the 10mg and 500mg doses, half-lives averaged approximately 1. 7 and 12 days, respectively. 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 Trastuzumab is The predicted steady-state clearance of trastuzumab is 0. 173 - 0. 337 L/day, dependent primarily on the dosing regimen. The clearance rate for subcutaneously administered trastuzumab, formulated with hyaluronidase for improved subcutaneous absorption, is 0. 11 L/day. 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. Trastuzumab toxicity includes There is no experience with overdosage of trastuzumab in clinical trials - single doses >8 mg/kg have not been tested in humans. Trastuzumab can contribute to the development of ventricular dysfunction and congestive heart failure, particularly when used in combination (or temporally adjacent) to other cardiotoxic chemotherapies such as anthracyclines. Brand names of Ofatumumab include Arzerra, Kesimpta. Brand names of Trastuzumab include Herceptin, Herceptin Hylecta, Herzuma, Kanjinti, Ontruzant, Perjeta-Herceptin, Phesgo, Trazimera. No synonyms are available for Ofatumumab. No synonyms are available for Trastuzumab. 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. Trastuzumab summary: It is Trastuzumab is a monoclonal anti-human epidermal growth factor receptor 2 protein antibody used to treat HER2-positive breast, gastroesophageal, and gastric cancers. Answer: While trastuzumab treatment itself can cause neutropenia, its co-administration with other immunosuppressive agents has been shown to result in synergistic neutropenic effects. In randomized controlled clinical trials, patients receiving trastuzumab in combination with myelosuppressive chemotherapy had higher rates of moderate to severe neutropenia and febrile neutropenia compared to those receiving chemotherapy alone. The pathophysiologic basis for this exacerbation of neutropenia has not been determined.

Ofatumumab

Drug A is Dulaglutide. Drug B is Brentuximab vedotin. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Brentuximab vedotin is combined with Dulaglutide. 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. Dulaglutide is indicated for Dulaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients ≥10 years of age with type 2 diabetes mellitus. It is also indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors. 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. Dulaglutide pharmacodynamics: Dulaglutide reduces fasting glucose concentrations and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus through the agonism of the GLP-1 receptor. This drug primarily acts as an incretin mimetic hormone or analog of human glucagon-like peptide-1, which normally acts on the GLP-1 receptor. 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. The mechanism of action of Dulaglutide is that it Dulaglutide activates the GLP-1 receptor found in pancreatic beta cells, increasing intracellular cyclic AMP (cAMP) in beta cells, leading to insulin release and subsequent reduction of blood glucose concentrations. Additionally, dulaglutide decreases glucagon secretion and slows gastric emptying. 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. Dulaglutide absorption: Dulaglutide is slowly absorbed after subcutaneous injection. In a pharmacokinetic study of 20 healthy adults, Cmax occurred within 24-48 hours after dosing. The average absolute bioavailability of dulaglutide after subcutaneous injections of single 0. 75 mg and 1. 5 mg doses was 65% and 47%, respectively. 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. The volume of distribution of Dulaglutide is The apparent volume of distribution of dulaglutide was 3. 09 L in a pharmacokinetic study; the apparent population mean peripheral volume of distribution was approximately 6 L. 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. Dulaglutide is Protein binding information for dulaglutide is not readily available in the literature. bound to plasma proteins. Brentuximab vedotin is In vitro, the binding of MMAE to human plasma proteins is in the range of 68–82%. bound to plasma proteins. Dulaglutide metabolism: Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways. 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. Dulaglutide is eliminated via Elimination of dulaglutide is expected to occur through degradation to individual amino acids. 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. The half-life of Dulaglutide is In a pharmacokinetic study of 20 healthy adults, the average half-life of dulaglutide administered at various doses was approximately 3. 75 days (89. 9 hours). This extended half-life allows for once-weekly dosing. Prescribing information indicates a half-life of approximately 5 days. The half-life of Brentuximab vedotin is The terminal half-life is approximately 4-6 days. The clearance of Dulaglutide is The apparent population mean clearance of dulaglutide was 0. 142 L/h in a pharmacokinetic study. 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). Dulaglutide toxicity includes LD50 information for dulaglutide is not readily available in the literature. Cases of overdose with dulaglutide have resulted in gastrointestinal disturbance. Appropriate supportive treatment is recommended to manage signs and symptoms. Additionally, hypoglycemia has been observed after an overdose with dulaglutide; frequent plasma glucose monitoring should be performed. 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. Brand names of Dulaglutide include Trulicity. Brand names of Brentuximab vedotin include Adcetris. No synonyms are available for Dulaglutide. No synonyms are available for Brentuximab vedotin. Dulaglutide summary: It is Dulaglutide is a GLP-1 agonist used to manage type 2 diabetes mellitus. Brentuximab vedotin summary: It is Brentuximab vedotin is a CD30-directed antibody-drug conjugate used to treat various types of 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.

Dulaglutide

Drug A is Bimekizumab. Drug B is Sonidegib. The severity of the interaction is major. The metabolism of Sonidegib 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 CYP3A4 substrates with a narrow therapeutic index. 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. Sonidegib is indicated for Sonidegib is approved for use in the US and EU for treatment of adults with locally advanced basal cell carcinoma (BCC) that has recurred post surgery or radiation therapy. It is also approved for adult patients with BCC who are not eligible for surgery or radiation therapy. (2). 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. Sonidegib pharmacodynamics: Sonidegib has been shown to inhibit a transmembrane protein called SMO which plays a role in Hh signal transduction. This has resulted in inhibition of Hh signaling as well as antitumour activity in various animal models. In a transgenic mouse model of islet cell neoplasms, tumour volume was reduce by 95% in mice treated with sonidegib when compared with untreated mice. (2). 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 Sonidegib is that it The hedgehog pathway is involved in many human cancers. Sonidegib effectively inhibits the regulator called smoothened (Smo), preventing the hedgehog pathway from functioning. As a result, tumours that depend on the hedgehog pathway are unable to grow. (1). Bimekizumab absorption: In healthy volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70. 1%. Sonidegib absorption: Sonidegib is rapidly absorbed in the fasted state with peak concentrations occurring 2-4 hours after administration. (2) However, the total absorption of Sonidegib is low (roughly 6-7%). (1). The volume of distribution of Bimekizumab is In patients with plaque psoriasis, the median volume of distribution at steady-state was 11. 2 L. The volume of distribution of Sonidegib is Estimated volume of distribution = 9166 L (2). No protein binding information is available for Bimekizumab. Sonidegib is Sonidegib is over 97% bound to plasma proteins, and binding is independent of concentration. (2) bound to plasma proteins. Bimekizumab metabolism: As a monoclonal antibody, bimekizumab is likely degraded into smaller peptides and amino acids via catabolic processes. Sonidegib metabolism: Sonidegib is primarily metabolized via oxidation and amide hydrolysis. (1) The enzyme responsible for the majority of metabolism is the cytochrome P450 (CYP) 3A4 enzyme. (2). Bimekizumab is eliminated via No route of elimination available. Sonidegib is eliminated via Around 70% of Sonidegib is eliminated in the feces, while 30% is eliminated in the urine. (2). 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 Sonidegib is Half-life ~ 28 days (2). 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 Sonidegib. 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. Sonidegib toxicity includes Adverse events occurred more frequently with higher doses, 800 mg once daily when compared to a lower dose of 200 mg once daily. In the 200 mg group, frequent adverse events (occurring in ≥2% of patients) included: elevated creatine phosphokinase (6%), increased lipase (5%), muscle spasms (3%), asthenia (3%), and hypertension (3%). In the 800 mg group, frequent adverse events included: elevated creatine phosphokinase (13%), increased lipase (5%), weight loss (5%), muscle spasms (5%), decreased appetite (4%), rhabdomyolysis (3%), nausea (3%), hypertension (3%), increased alanine aminotransferase (3%), increased aspartate aminotransferase (3%), fatigue (2%), syncope (2%), anaemia (2%), dehydration (2%), hyperkalaemia (2%) and myalgia (2%). Rhabdomyolysis cases reported by investigators were not confirmed by the adjudication committee on muscle toxicity or the independent safety review. (2). Brand names of Bimekizumab include No brand names available. Brand names of Sonidegib include Odomzo. No synonyms are available for Bimekizumab. No synonyms are available for Sonidegib. Sonidegib Bimekizumab summary: It is Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment plaque psoriasis. Sonidegib summary: It is Sonidegib is an antineoplastic agent used for the treatment of locally advanced recurrent basal cell carcinoma (BCC) following surgery and radiation therapy, or in cases where surgery or radiation therapy are not appropriate. 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.

Bimekizumab

Drug A is Budesonide. Drug B is Eszopiclone. The severity of the interaction is moderate. The serum concentration of Eszopiclone can be decreased when it is combined with Budesonide. Eszopiclone is a substrate of the CYP3A4 enzyme. Inducers of this enzyme, such as rifampicin, can cause a clinically significant decrease in eszopiclone levels due to increased metabolism. This may reduce the therapeutic effects of eszopiclone. 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. Eszopiclone is indicated for Eszopiclone is indicated for the treatment of insomnia. 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. Eszopiclone pharmacodynamics: Eszopiclone rapidly induces sleep and decreases sleep latency. It also aids in the maintenance of sleep, preventing frequent awakenings. This drug has shown anticonvulsant and muscle relaxant properties in animals but is used in humans for its sedating effects. Eszopiclone is a central nervous system depressant with various effects. These include changes in alertness and motor coordination and the risk of next morning impairment, increasing with the amount of eszopiclone administered. Exercise caution and advise against driving a motor vehicle or activities that require full mental alertness the next morning. Complex sleep behaviors may result from eszopiclone use. Eszopiclone should be discontinued in these cases. Avoid the use of alcohol and other CNS depressants when eszopiclone is administered. Advise patients to skip the eszopiclone dose if alcohol has been consumed before bed or during the evening. Use the smallest dose of eszopiclone as possible, especially in elderly patients, who may experience exaggerated drug effects. Though the potential for dependence and abuse with eszopiclone is lower than for other hypnotic drugs, this drug has been abused and is known to cause dependence. 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 Eszopiclone is that it The exact mechanism of action of eszopiclone is unknown at this time but is thought to occur via binding with the GABA receptor complexes at binding sites located near benzodiazepine receptors, possibly explaining its hypnotic and sedative effects. It has particular affinity for GABA-A (or GABAA) receptor subunits 1, 3 and 5. Eszopiclone increases GABA-A channel currents significantly. GABA-A channels are major inhibitory channels that cause CNS depression when their receptors are activated. 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. Eszopiclone absorption: Eszopiclone is rapidly absorbed and the peak concentration is reached within about 1 hour after oral administration. The mean AUC after a 3 mg dose of eszopiclone was 278 ng/mL × h. The consumption of a high-fat has been shown to slow absorption. Steady-state concentrations of eszopiclone are reached within 24-48 hours. The volume of distribution of Budesonide is The volume of distribution of budesonide is 2. 2-3. 9L/kg. The volume of distribution of Eszopiclone is The volume of distribution of eszopiclone is estimated at 89. 9L. 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. Eszopiclone is This drug is 52-59% bound to plasma proteins. 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. Eszopiclone metabolism: Following oral administration, eszopiclone is extensively biotransformed and the major metabolites are S-desmethylzopiclone and zopiclone-N-oxide, which are largely inactive. The enzymes involved in the metabolism of eszopiclone are CYP3A (the primary metabolizing enzyme), CYP2C8, and CYP2E1. The N-oxide derivative shows weak pharmacological activity in animals. The N-desmethyl metabolite is pharmacologically active. 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. Eszopiclone is eliminated via Only about 10% of an eszopiclone dose is found excreted in the urine as the parent drug. As much as 75% of an orally administered dose of racemic zopiclone as is found to be excreted in the urine in the form of metabolites. Eszopiclone, the S-isomer of racemic zopiclone, would likely show the same excretion pattern. 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 Eszopiclone is The half-life is 6. 1 hours in healthy patients but is prolonged in various patients, including those with hepatic impairment, elderly patients, in addition to those taking CYP3A enzyme inhibiting drugs. 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 Eszopiclone is The mean clearance of eszopiclone in young, healthy volunteers was 184 mL/min in one pharmacokinetic study. 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. Eszopiclone toxicity includes The oral LD50 of eszopiclone in rats is 980 mg/kg and 3200 mg/kg in rabbits. Symptoms of overdose may include mental status changes and somnolence, demonstrating general exaggeration of the drug's pharmacological effects. Perform gastric lavage and offer supportive treatment if an overdose is suspected, including intravenous fluids as required. Flumazenil may be used. Vital signs should be closely monitored in addition to patient symptoms. Appropriate medical interventions should be employed. The possibility of an overdose with multiple drugs should be considered. Ensure to contact the local poison control center for the most updated management of hypnotic drug overdose. Brand names of Budesonide include Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris. Brand names of Eszopiclone include Lunesta. No synonyms are available for Budesonide. Budesonide No synonyms are available for Eszopiclone. Esopiclone Eszopiclone Budesonide summary: It is Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis. Eszopiclone summary: It is Eszopiclone is a sedative-hypnotic used in the treatment of insomnia, improving both the latency phase and the maintenance phase of sleep. Answer: Eszopiclone is a substrate of the CYP3A4 enzyme. Inducers of this enzyme, such as rifampicin, can cause a clinically significant decrease in eszopiclone levels due to increased metabolism. This may reduce the therapeutic effects of eszopiclone.

Budesonide

Drug A is Adefovir dipivoxil. Drug B is Bacillus calmette-guerin substrain russian BCG-I live antigen. The severity of the interaction is moderate. The therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with Adefovir dipivoxil. Most live vaccines contain viruses that have been attenuated (weakened) by laboratory modification. These attenuated viruses are intended to infect and replicate in the recipient and result in a protective immune response involving T-cells in the immune system without causing disease. Concurrent administration of antiviral drugs may inhibit the viral replication of live attenuated viral vaccines, decreasing their efficacy. 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. 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. 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. 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. 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] Adefovir dipivoxil is ≤4% over the adefovir concentration range of 0. 1 to 25 μg/mL 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. Adefovir dipivoxil is eliminated via Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion. 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 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] 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. Brand names of Adefovir dipivoxil include Hepsera. No synonyms are available for Adefovir dipivoxil. Adefovir pivoxil bis-POM PMEA Adefovir dipivoxil summary: It is Adefovir dipivoxil is a nucleotide analog used to treat chronic hepatitis B. Bacillus calmette-guerin substrain russian BCG-I live antigen summary: It is Summary not found. Answer: Most live vaccines contain viruses that have been attenuated (weakened) by laboratory modification. These attenuated viruses are intended to infect and replicate in the recipient and result in a protective immune response involving T-cells in the immune system without causing disease. Concurrent administration of antiviral drugs may inhibit the viral replication of live attenuated viral vaccines, decreasing their efficacy.

Adefovir dipivoxil

Drug A is Certolizumab pegol. Drug B is Burosumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Certolizumab pegol is combined with Burosumab. 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. 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. Burosumab is indicated for This drug is indicated for the treatment of X-linked hypophosphatemia with radiological evidence of bone disease in children of 1 year of age and older and adolescents with growing skeletons. 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. Burosumab pharmacodynamics: This drug has the ability to reduce the loss of phosphate, to improve pathologically low serum phosphate concentrations and other metabolic changes, as well as to reduce the severity of rickets as seen radiographically. In summary, this drug works to support of bone mineralization. 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 Burosumab is that it Burosumab is a recombinant human monoclonal antibody (IgG1) that both binds to and inhibits the actions of fibroblast growth factor 23 (FGF23). By inhibiting this growth factor, burosumab increases the tubular reabsorption of phosphate from the kidney and thus increases serum concentration of 1, 25 dihydroxy-Vitamin D. This form of vitamin D enhances intestinal absorption of phosphate and calcium, supporting bone mineralization. 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. Burosumab absorption: Burosumab absorption after subcutaneous injection sites into to the blood circulation is nearly complete. Following the subcutaneous route of administration, the time to reach maximum serum concentrations (Tmax) of burosumab is estimated at 5-10 days. The peak serum concentration (Cmax) and area under the concentration-time curve (AUC) of serum burosumab is proportional to the dose, over the dose range of 0. 1-2. 0 mg/kg. 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 Burosumab is Burosumab is comprised solely of amino acids and carbohydrates as a native immunoglobulin and is not likeluy to be eliminated by hepatic metabolic mechanisms. The metabolism of burosumab and elimination are expected to follow the immunoglobulin clearance pathways, which results in its degradation to smaller peptides and amino acids. Certolizumab pegol is Monoclonal antibodies are usually not required to have protein binding studies. bound to plasma proteins. No protein binding information is available for Burosumab. 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. Burosumab metabolism: Burosumab is composed solely of amino acids and carbohydrates as a native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids. 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. Burosumab is eliminated via Because of its molecular size, burosumab is not likely to be directly excreted. The half-life of Certolizumab pegol is The circulatory half-life of certolizumab is of 14 days. The half-life of Burosumab is About 19 days. 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 Burosumab is The clearance of burosumab depends on weight and is estimated to be 0. 290 L/day and 0. 136 L/day in a typical adult (70 kg) and pediatric (30 kg) XLH patient, respectively. 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. Burosumab toxicity includes The toxicity of Crysvita can be classified into several categories: Ectopic mineralisation: Clinically manifested by nephrocalcinosis, has been seen in patients with XLH treated with oral phosphorous and vitamin D analogues. These drugs should be stopped at least 1 week before starting burosumab treatment. Monitoring for signs and symptoms of nephrocalcinosis, e. g. by renal ultrasonography, is recommended at the beginning of treatment and at intervals of every 6 months for the first 12 months of treatment, and yearly thereafter. Regular monitoring of plasma alkaline phosphatases, Calcium, PTH, and creatinine is advised at 6 months intervals(every 3 months for children 1- 2 years) or as indicated. Monitoring of urine calcium and phosphate is suggested every 3 months. Hyperphosphatemia Fasting serum phosphate level must be followed due to the risk of hyperphosphatemia while taking this drug. To decrease the risk for ectopic mineralization, it is advised that fasting serum phosphate is aimed to be in the lower end of the normal reference range for any given age. Dose interruption and/or dose reduction may be required. Regular measurement of postprandial serum phosphate is advised. Serum parathyroid hormone increases Increases in serum parathyroid hormone have been measured in some XLH patients while undergoing treatment with burosumab. Regular measurement of serum parathyroid hormone is recommended. Injection site reactions Administration of burosumab, like other injections, can lead to local injection site reactions. Administration of this drug should cease in any patient experiencing severe injection site reactions and appropriate medical therapy administered. Hypersensitivity Burosumab should be discontinued if serious hypersensitivity reactions occur and appropriate medical treatment should be provided. Reproductive toxicity/pregnancy There are no or limited amount of data available from the use of burosumab in pregnant women. Studies in animals have demonstrated reproductive toxicity. Burosumab use is not advised during pregnancy and in women of childbearing potential/age currently not using contraception. Brand names of Certolizumab pegol include Cimzia. Brand names of Burosumab include Crysvita. No synonyms are available for Certolizumab pegol. No synonyms are available for Burosumab. 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. Burosumab summary: It is Burosumab is a fibroblast growth factor 23 blocking antibody used to treat X-linked hypophosphatemia. 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.

Certolizumab pegol

Drug A is Aceclofenac. Drug B is Nitrous oxide. The severity of the interaction is minor. The risk or severity of hypertension can be increased when Nitrous oxide is combined with Aceclofenac. Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity. Aceclofenac is indicated for Aceclofenac is indicated for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Nitrous oxide is indicated for No indication available. 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. Nitrous oxide pharmacodynamics: No pharmacodynamics available. 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 Nitrous oxide is that it Findings to date indicate that nitrous oxide induces opioid peptide release in the brain stem leading to the activation of descending noradrenergic neurones, which results in modulation of the nociceptive process in the spinal cord. Several receptor–effector mechanisms including dopamine receptors, α2 adrenoceptors, benzodiazepine receptors and -methyl- -aspartate (NMDA) receptors have been implicated although the relationship of one with the other is not known. 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. No absorption information is available for Nitrous oxide. The volume of distribution of Aceclofenac is The volume of distribution is approximately 25 L. No volume of distribution information is available for Nitrous oxide. Aceclofenac is It is reported to be highly protein-bound (>99%). bound to plasma proteins. No protein binding information is available for Nitrous oxide. 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. No metabolism information is available for Nitrous oxide. 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. Nitrous oxide is eliminated via No route of elimination available. The half-life of Aceclofenac is The mean plasma elimination half-life is approximately 4 hours. The half-life of Nitrous oxide is No half-life available. The clearance of Aceclofenac is The mean clearance rate is approximately 5 L/h. No clearance information is available for Nitrous oxide. 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. No toxicity information is available for Nitrous oxide. Brand names of Aceclofenac include No brand names available. Brand names of Nitrous oxide include Alnox. No synonyms are available for Aceclofenac. Acéclofénac Aceclofenac betadex Aceclofenaco Aceclofenacum No synonyms are available for Nitrous oxide. Nitrious oxide Nitrous oxide óxido nitroso Aceclofenac summary: It is No summary available. Nitrous oxide summary: It is Nitrous oxide is an inhalatory gas used as an adjunct to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in certain neonates with hypoxic respiratory failure. Answer: Concurrent use of drugs known to increase blood pressure is expected to result in an increased risk for supine hypertension. Closely monitor the patient for elevated blood pressure (including in supine and head-elevated positions) and for any evidence of toxicity.

Aceclofenac

Drug A is Budesonide. Drug B is Dextromethorphan. The severity of the interaction is moderate. The metabolism of Dextromethorphan can be increased when combined with Budesonide. The subject is a moderate inducer of the CYP3A5 enzyme, and the affected drug is a substrate of the CYP3A5 enzyme. When these drugs are administered concomitantly, the metabolism of the affected drug is increased, decreasing serum concentrations and lowering the efficacy. 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. Dextromethorphan is indicated for Dextromethorphan is indicated in combination with brompheniramine and pseudoephedrine in the treatment of coughs and upper respiratory symptoms associated with allergies or the common cold. Dextromethorphan is also used in combination with guaifenesin as an over-the-counter product to relieve a cough. Dextromethorphan in combination with quinidine is indicated in the treatment of pseudobulbar affect. 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. Dextromethorphan pharmacodynamics: Dextromethorphan is an opioid-like molecule indicated in combination with other medication in the treatment of coughs and pseudobulbar affect. It has a moderate therapeutic window, as intoxication can occur at higher doses. Dextromethorphan has a moderate duration of action. Patients should be counselled regarding the risk of intoxication. 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 Dextromethorphan is that it Dextromethorphan is an agonist of NMDA and sigma-1 receptors. It is also an antagonist of α3/β4 nicotinic receptors. However, the mechanism by which dextromethorphan's receptor agonism and antagonism translates to a clinical effect is not well understood. 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. Dextromethorphan absorption: A 30mg oral dose of dextromethorphan reaches a Cmax of 2. 9 ng/mL, with a Tmax of 2. 86 h, and an AUC of 17. 8 ng*h/mL. The volume of distribution of Budesonide is The volume of distribution of budesonide is 2. 2-3. 9L/kg. The volume of distribution of Dextromethorphan is The volume of distribution of dextromethorphan is 5-6. 7L/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. Dextromethorphan is Dextromethorphan is 60-70% protein bound in serum. 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. Dextromethorphan metabolism: Dextromethorphan can be N-demethylated to 3-methoxymorphinan by CYP3A4, CYP2D6, and CYP2C9 or O-demethylated to dextrorphan by CYP2D6 and CYP2C9. Dextrorphan is N-demethylated by CYP3A4 and CYP2D6, while 3-methoxymorphinan is O-demethylated by CYP2D6. Both are metabolized to form 3-hydroxymorphinan. Dextrorphan and 3-hydroxymorphinan are both O-glucuronidated or O-sulfated. 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. Dextromethorphan is eliminated via No route of elimination available. 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 Dextromethorphan is Dextromethorphan has a half life of 3-30 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. No clearance information is available for Dextromethorphan. 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. Dextromethorphan toxicity includes A dextromethorphan overdose may present as nausea, vomiting, stupor, coma, respiratory depression, seizures, tachycardia, hyperexcitability, toxic psychosis, ataxia, nystagmus, dystonia, blurred vision, changes in muscle reflexes, and serotonin syndrome. Overdose should be managed through symptomatic and supportive measures. Brand names of Budesonide include Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris. Brand names of Dextromethorphan include Auvelity, Benylin DM, Bromfed DM, Broncotron, Cepacol Sore Throat Plus Cough, Cheracol D, Children's Nyquil Cold and Cough, Chloraseptic Sore Throat + Cough, Coricidin Hbp Chest Congestion, Coricidin Hbp Cough and Cold, Creomulsion, DM, Dayquil Cough, Delsym, Delsym Cough Plus Chest Congestion DM, Delsym Cough Plus Soothing Action, Delsym Cough Relief Plus Soothing Action, Despec Reformulated Jun 2008, Diabetic Tussin DM, Dimetapp Long Acting Cough Plus Cold, Diphen, G-zyncof, Mucinex Children's Cough, Mucinex Cough, Mucinex DM, Nuedexta, Nyquil Cough, Pediacare Children's Cough and Congestion, Promethazine DM, Robafen Cough, Robafen DM, Robitussin 12 Hour Cough Relief, Robitussin Cough & Congestion, Robitussin Maximum Strength Cough Plus Chest Congestion DM, Robitussin Nighttime Cough DM, Robitussin Pediatric Cough & Cold LA, Robitussin Pediatric Cough Suppressant, Safetussin DM, Safetussin PM, Scot-tussin DM, Scot-tussin Diabetic CF, Scot-tussin Sugar Free DM, Sudafed PE Children's Cold & Cough, Triaminic Day Time Cold & Cough, Tusnel Diabetic. No synonyms are available for Budesonide. Budesonide No synonyms are available for Dextromethorphan. delta-Methorphan Dextromethorfan Dextromethorphan Dextrométhorphane Dextromethorphanum Dextrometorfano Budesonide summary: It is Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis. Dextromethorphan summary: It is Dextromethorphan is an NMDA receptor antagonist used to treat cases of dry cough. Answer: The subject is a moderate inducer of the CYP3A5 enzyme, and the affected drug is a substrate of the CYP3A5 enzyme. When these drugs are administered concomitantly, the metabolism of the affected drug is increased, decreasing serum concentrations and lowering the efficacy.

Budesonide

Drug A is Pegaspargase. Drug B is Interferon alfa-n3. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Interferon alfa-n3 is combined with Pegaspargase. Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Pegaspargase is indicated for Pegaspargase is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of pediatric and adult patients with 1) first-line acute lymphoblastic leukemia or 2) acute lymphoblastic leukemia and hypersensitivity to asparaginase. Interferon alfa-n3 is indicated for the intralesional treatment of refractory or recurring external condylomata acuminata. Pegaspargase pharmacodynamics: Unlike normal cells, leukemia cells are dependent on an exogenous source of asparagine for survival. Pegaspargase hydrolyses asparagine into aspartic acid and ammonia, which depletes asparagine levels and leads to leukaemic cell death. In patients given intramuscular doses of 2,500 International Units(IU)/m of pegaspargase, the serum levels of asparagine fall at day 4 and remain depleted for about 3 weeks. In adult patients with acute lymphocytic leukemia given 2,000 IU/m of pegaspargase intravenously, the deamination of asparagine takes place 2 h after administration and is sustained for 3 weeks, while in pediatric patients given 2,500 IU/m, levels are sustained for 5 weeks. The use of pegaspargase may lead to thrombosis, pancreatitis, glucose intolerance, hemorrhage, hepatotoxicity, anaphylaxis and serious hypersensitivity reactions. Interferon alfa-n3 pharmacodynamics: Interferon alfa-n3 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), beta-2 microglobulin, neopterin and protein kinase R. The mechanism of action of Pegaspargase is that it Pegaspargase is a pegylated L-asparaginase that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. Asparagine is an amino acid that is vital for DNA and RNA synthesis and cell division. It is not an essential amino acid in humans since most normal human tissues can produce asparagine via the enzyme asparagine synthetase. However, leukemia cells have low levels of this enzyme and are unable to synthesize asparagine, making them dependent on exogenous sources. It has been suggested that pegaspargase kills leukemic cells by depleting plasma asparagine. Both Escherichia coli -derived L-asparaginase and pegaspargase follow the same mechanism of action; however, Escherichia coli -derived L-asparaginase requires frequent administration, presents a high incidence of hypersensitivity reactions, and can be neutralized without any signs of hypersensitivity. By pegylating L-asparaginase, the circulation time of L-asparaginase can be extended, and immunogenicity is reduced. The mechanism of action of Interferon alfa-n3 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. Pegaspargase absorption: In patients with acute lymphoblastic leukemia given 2,500 International Units (IU)/m of pegaspargase, the mean asparaginase Cmax was reached at approximately 1 IU/mL (n=45-52) five days after a single intramuscular injection. Pegaspargase had a relative bioavailability of 82% after the first intramuscular dose and 98% following repeat dosing. In patients given pegaspargase intravenously in a single infusion (n=47) during the induction phase, the mean Cmax and AUC 0-inf were 1. 6 IU/mL and 16. 6 IU/mL⋅day, respectively. The Tmax for these patients was 1. 25 hr. The impact of renal and hepatic impairment on pegaspargase pharmacokinetics is unknown. No absorption information is available for Interferon alfa-n3. The volume of distribution of Pegaspargase is Based on a non-compartmental analysis, pegaspargase has a steady-state volume of distribution of approximately 1. 86 L/m2 after a single intramuscular injection and 2 L after a single intravenous infusion. No volume of distribution information is available for Interferon alfa-n3. No protein binding information is available for Pegaspargase. No protein binding information is available for Interferon alfa-n3. Pegaspargase metabolism: As a pegylated form of L-asparaginase, pegaspargase is expected to be metabolized by proteolytic enzymes throughout the body. Since these enzymes are ubiquitously distributed, the exact role of the liver is unknown. No metabolism information is available for Interferon alfa-n3. Pegaspargase is eliminated via Due to its high molecular weight, pegaspargase is not excreted renally. Interferon alfa-n3 is eliminated via No route of elimination available. The half-life of Pegaspargase is The mean elimination half-life of pegaspargase was approximately 5. 8 days after a single intramuscular dose, and 5. 3 days after a single intravenous dose. The half-life of Interferon alfa-n3 is No half-life available. The clearance of Pegaspargase is a single intramuscular and intravenous dose, the clearance of pegaspargase is 0. 17 L/m2/day and 0. 2 L/day, respectively. No clearance information is available for Interferon alfa-n3. Pegaspargase toxicity includes Patients that received 10,000 International Units/m of pegaspargase intravenously, had a slight increase in liver enzymes and a rash that developed 10 minutes after the start of the infusion, which was controlled with the administration of an antihistamine and by slowing down the infusion rate. There is no specific antidote for pegaspargase overdosage. The product label recommends to monitor patients closely for signs and symptoms of adverse reactions, and appropriately manage with symptomatic and supportive treatment in case of overdose. The carcinogenic, mutagenic and fertility effects of pegaspargase have not been evaluated. No toxicity information is available for Interferon alfa-n3. Brand names of Pegaspargase include Oncaspar. Brand names of Interferon alfa-n3 include Alferon N. No synonyms are available for Pegaspargase. No synonyms are available for Interferon alfa-n3. Pegaspargase summary: It is Pegaspargase is a modified form of L-asparagine amidohydrolase used to treat acute lymphoblastic leukemia, which is dependent on an external source of asparagine. Interferon alfa-n3 summary: It is Interferon alfa-n3 is a purified form of human interferon used to stimulate the innate antiviral response in the treatment of genital warts due to human papilloma virus. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Pegaspargase

Drug A is Acetazolamide. Drug B is Tiotropium. The severity of the interaction is moderate. Acetazolamide may increase the excretion rate of Tiotropium 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. Acetazolamide is indicated for adjunctive treatment of: edema due to congestive heart failure; drug-induced edema; centrencephalic epilepsies; chronic simple (open-angle) glaucoma. Tiotropium is indicated for Tiotropium powder for inhalation is indicated for the maintenance of bronchospasm in COPD and to prevent exacerbations of COPD. A combination tiotropium and olodaterol metered inhalation spray is indicated for maintenance of COPD. A tiotropium inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 12 or more years old. A tiotropium metered inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 6 or more years old. 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. Tiotropium pharmacodynamics: Tiotropium is a long acting antimuscarinic that causes bronchodilation. The effects of tiotropium last over 24 hours and there is a wide therapeutic index as overdoses are uncommon even at doses well above the recommended maximum. 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 Tiotropium is that it Tiotropium is an antagonist of muscarinic receptors M 1 to M 5. Inhibition of the M 3 receptor in the smooth muscle of the lungs leads to relaxation of smooth muscle and bronchodilation. No absorption information is available for Acetazolamide. Tiotropium absorption: 33% of an inhaled solution reaches systemic circulation, while oral solutions have a bioavailability of 2-3%. A dry powder for inhalation is 19. 5% bioavailable. Tiotropium metered spray for inhalation reaches a maximum concentration in 5-7 minutes. No volume of distribution information is available for Acetazolamide. The volume of distribution of Tiotropium is The volume of distribution of tiotropium is 32L/kg. Acetazolamide is 98% bound to plasma proteins. Tiotropium is Tiotropium is 72% protein bound in plasma. bound to plasma proteins. No metabolism information is available for Acetazolamide. Tiotropium metabolism: Tiotropium is not heavily metabolized in the body. 74% of an intravenous dose is excreted in the urine as unchanged drug. Tiotropium is nonenzymatically cleaved to the inactive metabolites N-methylscopine and dithienylglycolic acid. In vitro experiments show cytochrome P-450 dependent oxidation and glutathione conjugation to further metabolites. Acetazolamide is eliminated via No route of elimination available. Tiotropium is eliminated via 74% of intravenous tiotropium was excreted unchanged in urine. 14% of a dry powder inhalation dose was excreted unchanged in the urine. 24 hour urinary excretion after 21 days of 5µg once daily inhalation in patients with COPD is 18. 6% and in patients with asthma is 12. 8%. The half-life of Acetazolamide is 3 to 9 hours. The half-life of Tiotropium is The terminal half life of tiotropium is 24 hours in patients with COPD and 44 hours in patients with asthma. No clearance information is available for Acetazolamide. The clearance of Tiotropium is The total clearance of tiotropium is 880mL/min in healthy subjects receiving 5µg daily. The renal clearance of tiotropium was 669mL/min. Patients <65 years old demonstrated a clearance of 365mL/min while patients ≥65 demonstrated a clearance of 271mL/min. This decreased clearance is not associated with increased AUC or Cmax. No toxicity information is available for Acetazolamide. Tiotropium toxicity includes Symptoms of overdose include altered mental status, tremors, abdominal pain, and severe constipation. However, doses of up to 282µg did not lead to systemic anticholinergic effects in a trial of 6 patients. In case of overdose, stop tiotropium and being symptomatic and supportive therapy. Brand names of Acetazolamide include No brand names available. Brand names of Tiotropium include Inspiolto Respimat, Spiriva, Spiriva Respimat, Stiolto. No synonyms are available for Acetazolamide. Acetazolamida Acétazolamide Acetazolamide Acetazolamidum No synonyms are available for Tiotropium. 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. Tiotropium summary: It is Tiotropium is a long-acting bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). 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.

Acetazolamide

Drug A is Octreotide. Drug B is Ranolazine. The severity of the interaction is minor. The risk or severity of QTc prolongation can be increased when Octreotide is combined with Ranolazine. 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. 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. Ranolazine is indicated for Ranolazine is indicated for the treatment of chronic angina. It can be used alone or in conjunction with nitrates, beta-blockers, angiotensin receptor blockers, anti-platelet drugs, calcium channel blockers, lipid-lowering drugs, and ACE inhibitors. Ranolazine has also been used off-label for the treatment of certain arrhythmias, including ventricular tachycardia, however, this use is not strongly supported by scientific evidence. Ranolazine has also been studied for the treatment of acute coronary syndrome, microvascular coronary dysfunction, arrhythmia, and glycemic control, which are not yet approved indications. 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. Ranolazine pharmacodynamics: Ranolazine exerts both antianginal and ischemic effects independent from lowering heart rate or blood pressure. It blocks IKr, the rapid portion of the delayed rectifier potassium current, and prolongs the QTc interval in a dose-dependent fashion. The Ikr is important for cardiac repolarization. Ranolazine exerts its therapeutic effects without negative chronotropic, dromotropic, or inotropic actions neither at rest, nor during exercise. 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 Ranolazine is that it Myocardial ischemia exerts effects on adenosine triphosphate flux, leading to a decrease in the energy available for contraction and relaxation of the heart muscle. Electrolyte balance of sodium and potassium is necessary for maintaining normal cardiac contraction and relaxation. Disruption of adequate sodium and potassium electrolyte balance leads to excessively high concentrations of sodium and calcium, which likely interferes with oxygen supply to the heart muscle. This imbalance eventually leads to angina symptoms of chest pain or pressure, nausea, and dizziness, among others. The mechanism of action for ranolazine is not fully understood. At therapeutic concentrations, it can inhibit the cardiac late sodium. 205 current (INa), which may affect the electrolyte balance in the myocardium, relieving angina symptoms. The clinical significance this inhibition in the treatment of angina symptoms is not yet confirmed. Ranolazine inhibits sodium and potassium ion channel currents. It has been shown to exert weak activity on L-type calcium channels making it a weak direct vasodilator and exerts minimal direct effects on atrioventricular nodal conduction. Some additional mechanisms have been elucidated. Ranolazine exerts antagonistic activity towards the alpha 1 and beta 1 adrenergic receptors and inhibition of fatty acid oxidation. 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. Ranolazine absorption: The time to reach peak serum concentration is quite variable but has been observed to be in the range of 2-6 hours, with steady-state within 3 days. The FDA indicates a Tmax of 3-5 hours. The average steady-state Cmax is about 2600 ng/mL. Absorption of ranolazine is not significantly affected by food consumption. The bioavailability of ranolazine taken in the tablet form compared to that from a solution of ranolazine is about 76%. 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 Ranolazine is The mean apparent volume of distribution of ranolazine is reported to be 53. 2 L and the average steady-state volume of distribution is estimated to range from 85 to 180 L. Octreotide is Approximately 65% of the dose is bound in the plasma to lipoproteins and albumin. bound to plasma proteins. Ranolazine is Approximately 62% of the administered dose of ranolazine is bound to plasma proteins. Ranolazine appears to have a higher binding affinity for alpha-1 acid glycoprotein. bound to plasma proteins. Octreotide metabolism: Octreotide has been reported to be heavily metabolized in the liver. Ranolazine metabolism: Ranolazine is rapidly heavily metabolized in the liver an gastrointestinal tract through the activity of the CYP3A4 enzyme with minor contributions from CYP2D6. More than 40 ranolazine metabolites have been found in plasma and more than 100 metabolites have been identified in the urine. Ranolazine and some of its metabolites are known to weakly inhibit CYP3A4. However, the activity of the metabolites of ranolazine has not been fully elucidated. 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. Ranolazine is eliminated via From the administered dose, about 3/4 of the dose is excreted renally, while 1/4 of the dose is excreted in the feces. An estimated 5% of an ingested dose is excreted as unchanged drug. 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 Ranolazine is The apparent terminal half-life of ranolazine is 7 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 Ranolazine is The reported clearance rate of orally administered ranolazine is of 45 L/h when administered at a dose of 500 mg twice daily. The clearance rate of ranolazine is dose-dependent and renal impairment can increase ranolazine serum concentration by 40-50%. 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. Ranolazine toxicity includes The reported LD50 of oral ranolazine in the rat is 980 mg/kg. High oral doses of ranolazine have led to dizziness, nausea, and vomiting. These effects have been shown to be dose related. High intravenous doses can cause diplopia, confusion, paresthesia, in addition to syncope. In. the case of an overdose, provide supportive therapy accompanied by continuous ECG monitoring for QT interval prolongation. Brand names of Octreotide include Bynfezia, Mycapssa, Sandostatin. Brand names of Ranolazine include Aspruzyo Sprinkle, Ranexa. No synonyms are available for Octreotide. No synonyms are available for Ranolazine. 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. Ranolazine summary: It is Ranolazine is an anti-anginal drug used for the treatment of chronic angina. 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.

Octreotide

Drug A is Belantamab mafodotin. Drug B is Losartan. The severity of the interaction is moderate. Losartan 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. Losartan is indicated for Losartan is indicated to treat hypertension in patients older than 6 years, reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage), and to treat diabetic nephropathy with elevated serum creatinine and proteinuria in patients with type 2 diabetes and hypertension. Losartan with hydrochlorothiazide is indicated to treat hypertension and to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage). 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. Losartan pharmacodynamics: Losartan is an angiotensin II receptor blocker used to treat hypertension, diabetic nephropathy, and to reduce the risk of stroke. Losartan has a long duration of action as it is given once daily. Patients taking losartan should be regularly monitored for hypotension, renal function, and potassium levels. 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 Losartan is that it Losartan reversibly and competitively prevents angiotensin II binding to the AT 1 receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT 1 receptor with 1000 times more affinity than they bind to the AT 2 receptor. The active metabolite of losartan is 10-40 times more potent by weight than unmetabolized losartan as an inhibitor of AT 1 and is a non-competitive inhibitor. Losartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation, lowering blood pressure. Angiotensin II would otherwise bind to the AT 1 receptor and induce vasoconstriction, raising blood pressure. 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. Losartan absorption: Losartan is approximately 33% orally bioavailable. Losartan has a Tmax of 1 hour and the active metabolite has a Tmax of 3-4 hours. Taking losartan with food decreases the Cmax but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a Cmax of 200-250ng/mL. 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 Losartan is The volume of distribution of losartan is 34. 4±17. 9L and 10. 3±1. 1L for the active metabolite (E-3174). Belantamab mafodotin is Monoclonal antibodies are generally not protein bound. bound to plasma proteins. Losartan is Losartan is 98. 6-98. 8% protein bound and the active metabolite (E-3174) is 99. 7% protein bound in serum. 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. Losartan metabolism: Losartan is metabolized to an aldehyde intermediate, E-3179, which is further metabolized to a carboxylic acid, E-3174, by cytochrome P450s like CYP2C9. Losartan can also be hydroxylated to an inactive metabolite, P1. Approximately 14% of losartan is metabolized to E-3174. Losartan can be metabolized by CYP3A4, CYP2C9, and CYP2C10. Losartan can also be glucuronidated by UGT1A1, UGT1A3, UGT1A10, UGT2B7, and UGT 2B17. 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. Losartan is eliminated via A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% in feces. 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 Losartan is The terminal elimination half life of losartan is 1. 5-2. 5 hours while the active metabolite has a half life of 6-9 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. The clearance of Losartan is Losartan has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/min. Belantamab mafodotin toxicity includes Data regarding overdose is not readily available. However, keratopathy was seen in 71% of patients. Losartan toxicity includes The oral TDLO in mice is 1000mg/kg and in rats is 2000mg/kg. In humans the TDLO for men is 10mg/kg/2W and for women is 1mg/kg/1D. Symptoms of overdose are likely to include hypotension, tachycardia, or bradycardia due to vagal stimulation. Supportive treatment should be instituted for symptomatic hypotension. Hemodialysis will not remove losartan or its active metabolite due to their high rates of protein binding. Brand names of Belantamab mafodotin include BLENREP. Brand names of Losartan include Cozaar, Hyzaar. No synonyms are available for Belantamab mafodotin. No synonyms are available for Losartan. 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. Losartan summary: It is Losartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy, and is used to reduce the risk of 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.

Belantamab mafodotin

Drug A is Acetazolamide. Drug B is Baricitinib. The severity of the interaction is moderate. Acetazolamide may increase the excretion rate of Baricitinib 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. Acetazolamide is indicated for adjunctive treatment of: edema due to congestive heart failure; drug-induced edema; centrencephalic epilepsies; chronic simple (open-angle) glaucoma. Baricitinib is indicated for In the US and Europe, baricitinib 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 blockers. Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs. In Europe, baricitinib is indicated for the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy. In the US, baricitinib is also indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. Recently, it is also approved as the treatment for severe alopecia areata in adults. 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. Baricitinib pharmacodynamics: Baricitinib is a disease-modifying antirheumatic drug (DMARD) used to ameliorate symptoms and slow down the progression of rheumatoid arthritis. In animal models of inflammatory arthritis, baricitinib was shown to have significant anti-inflammatory effects but also led to the preservation of cartilage and bone, with no detectable suppression of humoral immunity or adverse hematologic effects. Baricitinib decreased the levels of immunoglobulins and serum C-reactive protein in patients with rheumatoid arthritis. 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 Baricitinib is that it As members of the tyrosine kinase family, Janus kinases (JAKs) are intracellular enzymes that modulate signals from cytokines and growth factor receptors involved in hematopoiesis, inflammation, and immune cell function. Upon binding of extracellular cytokines and growth factors, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs). STATs modulate intracellular activity, including gene transcription of inflammatory mediators that promote an autoimmune response, such as IL-2, IL-6, IL-12, IL-15, IL-23, IFN-γ, GM-CSF, and interferons. The JAK-STAT pathway has been implicated in the pathophysiology of rheumatoid arthritis, as it is associated with an overproduction of inflammatory mediators. There are four JAK proteins: JAK 1, JAK 2, JAK 3 and TYK2. JAKs form homodimers or heterodimers and pair differently in different cell receptors to transmit cytokine signaling. Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2 with less affinity for JAK3 and TYK2; however, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Baricitinib inhibits the activity of JAK proteins and modulates the signaling pathway of various interleukins, interferons, and growth factors. It was also shown to decrease the proliferation of JAK1/JAK2 expression in mutated cells and induce cell apoptosis. No absorption information is available for Acetazolamide. Baricitinib absorption: The absolute bioavailability of baricitinib is approximately 80%. The Cmax was reached after one hour of oral drug administration. A high-fat meal decreased the mean AUC and Cmax of baricitinib by approximately 11% and 18%, respectively, and delayed Tmax by 0. 5 hours. No volume of distribution information is available for Acetazolamide. The volume of distribution of Baricitinib is Following intravenous administration, the volume of distribution was 76 L, indicating distribution into tissues. Acetazolamide is 98% bound to plasma proteins. Baricitinib is Baricitinib is approximately 50% bound to plasma proteins and 45% bound to serum proteins. bound to plasma proteins. No metabolism information is available for Acetazolamide. Baricitinib metabolism: Baricitinib is metabolized by CYP3A4. Approximately 6% of the orally administered dose was identified as metabolites in urine and feces; however, no metabolites of baricitinib were quantifiable in plasma. Acetazolamide is eliminated via No route of elimination available. Baricitinib is eliminated via Baricitinib is predominantly excreted via renal elimination. It is cleared via filtration and active secretion. Approximately 75% of the administered dose was eliminated in the urine, with 20% of that dose being the unchanged drug. About 20% of the dose was eliminated in the feces, with 15% of that dose being an unchanged drug. The half-life of Acetazolamide is 3 to 9 hours. The half-life of Baricitinib is The elimination half-life in patients with rheumatoid arthritis is approximately 12 hours. The elimination half-life was 10. 8 hours in intubated patients with COVID-19 who received baricitinib via nasogastric (NG) or orogastric (OG) tube. No clearance information is available for Acetazolamide. The clearance of Baricitinib is The total body clearance of baricitinib was 8. 9 L/h in patients with rheumatoid arthritis. The total body clearance and half-life of baricitinib was 14. 2 L/h in intubated patients with COVID-19 who received baricitinib via nasogastric (NG) or orogastric (OG) tube. No toxicity information is available for Acetazolamide. Baricitinib toxicity includes The oral lowest published toxic dose (TDLo) is 1820 g/kg in mice and 5096 g/kg in rats. In clinical trials, single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days did not result in any dose-limiting toxicity. Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours. In case of an overdose, it is recommended that patients are monitored for signs and symptoms of drug-related adverse reactions, which should be responded with appropriate treatment. Brand names of Acetazolamide include No brand names available. Brand names of Baricitinib include Olumiant. No synonyms are available for Acetazolamide. Acetazolamida Acétazolamide Acetazolamide Acetazolamidum No synonyms are available for Baricitinib. 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. Baricitinib summary: It is Baricitinib is a Janus kinase inhibitor used to treat moderate to severe rheumatoid arthritis that has responded poorly to at least one TNF antagonist. 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.

Acetazolamide

Drug A is Abiraterone. Drug B is Promethazine. The severity of the interaction is moderate. The metabolism of Promethazine can be decreased when combined with Abiraterone. The subject drug is a moderate CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, leading to increased serum concentrations as well as increased 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. Promethazine is indicated for Promethazine tablets and suppositories are indicated to treat rhinitis, allergic conjunctivitis, allergic reactions to blood or plasma, dermographism, anaphylactic reactions, sedation, nausea, vomiting, pain, motion sickness, and allergic skin reactions. Promethazine cough syrup with phenylephrine and codeine is indicated to relieve cough and upper respiratory symptoms, and nasal congestion associated with allergy or the common cold. 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. Promethazine pharmacodynamics: Promethazine is a histamine H1 antagonist that can be used for it's ability to induce sedation, reduce pain, and treat allergic reactions. Promethazine's effects generally last 4-6h but can last up to 12h. Patients should be counselled regarding CNS and respiratory depression, reduce seizure threshold, and bone marrow depression. 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 Promethazine is that it Promethazine is a an antagonist of histamine H1, post-synaptic mesolimbic dopamine, alpha adrenergic, muscarinic, and NMDA receptors. The antihistamine action is used to treat allergic reactions. Antagonism of muscarinic and NMDA receptors contribute to its use as a sleep aid, as well as for anxiety and tension. Antagonism of histamine H1, muscarinic, and dopamine receptors in the medullary vomiting center make promethazine useful in the treatment of nausea and vomiting. 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. Promethazine absorption: A 25mg dose of intramuscular promethazine reaches a Cmax of 22ng/mL. Intravenous promethazine reaches a Cmax of 10. 0ng/mL, with a Tmax of 4-10h, and an AUC of 14,466ng*h/mL. Oral promethazine is only 25% bioavailable due to first pass metabolism. Oral promethazine reaches a Cmax of 2. 4-18. 0ng/mL, with a Tmax of 1. 5-3h, and an AUC of 11,511ng*h/mL. 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 Promethazine is The volume of distribution of promethazine is approximately 970L or 30L/kg. Abiraterone is Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. bound to plasma proteins. Promethazine is Promethazine is 93% protein bound in serum, mostly to albumin. 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. Promethazine metabolism: Promethazine is predominantly metabolized to promethazine sulfoxide, and minorly to desmethylpromethazine and a hydroxy metabolite. Hydroxylation of promethazine is predominantly mediated by CYP2D6. 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. Promethazine is eliminated via An intravenous dose of promethazine is 0. 64% eliminated in the urine as the unchanged parent drug, 0. 02-2. 02% in the urine as desmethylpromethazine, 10% in the urine as promethazine sulfoxide. 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 Promethazine is The elimination half life of promethazine is approximately 12-15h. No clearance information is available for Abiraterone. The clearance of Promethazine is The intravenous clearance of promethazine is approximately 1. 14L/min. The renal clearance of promethazine is 5. 9mL/min and the renal clearance of promethazine sulfoxide is 90. 4mL/min. 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. Promethazine toxicity includes The intraperitoneal LD 50 in rats is 170mg/kg and in mice is 160mg/kg. The subcutaneous LD 50 in rats is 400mg/kg and in mice is 240mg/kg. The oral LD 50 in mice is 255mg/kg. Patients experiencing an overdose of promethazine may present with mild central nervous system and cardiovascular depression, hypotension, respiratory depression, unconciousness, hyperreflexia, hypertonia, ataxia, athetosis, extensor-plantar reflexes, convulsions, dry mouth, flushing, gastrointestinal symptoms, and fixed, dilated pupils. Treat overdoses with symptomatic and supportive treatment, which may include activated charcoal, sodium sulfate, magnesium sulfate, controlled ventilation, diazepam, intravenous fluids, vasopressors, norepinephrine, phenylephrine, anticholinergic antiparkinsonian agents, diphenhydramine, barbiturates, or oxygen. Brand names of Abiraterone include Yonsa, Zytiga. Brand names of Promethazine include Phenadoz, Phenergan, Promethazine DM, Promethegan. No synonyms are available for Abiraterone. Abiraterone No synonyms are available for Promethazine. Prometazina Promethazine Promethazinum 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. Promethazine summary: It is Promethazine is a first-generation antihistamine used for the treatment of allergic conditions, nausea and vomiting, and motion sickness. Answer: The subject drug is a moderate CYP2D6 inhibitor and the affected drug is metabolized by CYP2D6. Concomitant administration may decrease the metabolism of the affected drug, leading to increased serum concentrations as well as increased risk and severity of adverse effects.

Abiraterone

Drug A is Abrocitinib. Drug B is Rosuvastatin. The severity of the interaction is minor. The metabolism of Abrocitinib can be decreased when combined with Rosuvastatin. Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of 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. Rosuvastatin is indicated for The FDA monograph states that rosuvastatin is indicated as an adjunct to diet in the treatment of triglyceridemia, Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia), and Homozygous Familial Hypercholesterolemia. The Health Canada monograph for rosuvastatin further specifies that rosuvastatin is indicated for the reduction of elevated total cholesterol (Total-C), LDL-C, ApoB, the Total-C/HDL-C ratio and triglycerides (TG) and for increasing HDL-C in hyperlipidemic and dyslipidemic conditions when response to diet and exercise alone has been inadequate. It is also indicated for the prevention of major cardiovascular events (including risk of myocardial infarction, nonfatal stroke, and coronary artery revascularization) in adult patients without documented history of cardiovascular or cerebrovascular events, but with at least two conventional risk factors for cardiovascular disease. Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD. Statin-indicated conditions include diabetes mellitus, clinical atherosclerosis (including myocardial infarction, acute coronary syndromes, stable angina, documented coronary artery disease, stroke, trans ischemic attack (TIA), documented carotid disease, peripheral artery disease, and claudication), abdominal aortic aneurysm, chronic kidney disease, and severely elevated LDL-C levels. 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. Rosuvastatin pharmacodynamics: Rosuvastatin is a synthetic, enantiomerically pure antilipemic agent. It is used to lower total cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, rosuvastatin reduces the risk of cardiovascular morbidity and mortality. Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD. Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality. Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack. Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks. Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. These risks can occur at any dose level, but are increased at the highest dose (40 mg). Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy (e. g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of some other lipid-lowering therapies (such as fenofibrate or niacin ), gemfibrozil, cyclosporine, atazanavir / ritonavir, lopinavir /ritonavir, or simeprevir. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should therefore be exercised when prescribing these two medications together. Real-world data from observational studies has suggested that 10-15% of people taking statins may experience muscle aches at some point during treatment. Liver Enzyme Abnormalities Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including rosuvastatin. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials. Endocrine Effects Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium tablets. Based on clinical trial data with rosuvastatin, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus. An in vitro study found that atorvastatin, pravastatin, rosuvastatin, and pitavastatin exhibited a dose-dependent cytotoxic effect on human pancreas islet β cells, with reductions in cell viability of 32, 41, 34 and 29%, respectively, versus control]. Moreover, insulin secretion rates were decreased by 34, 30, 27 and 19%, respectively, relative to control. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Rosuvastatin demonstrated no effect upon nonstimulated cortisol levels and no effect on thyroid metabolism as assessed by TSH plasma concentration. In rosuvastatin treated patients, there was no impairment of adrenocortical reserve and no reduction in plasma cortisol concentrations. Clinical studies with other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma testosterone concentration. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied. The effects, if any, on the pituitarygonadal axis in premenopausal women are unknown. Cardiovascular Ubiquinone levels were not measured in rosuvastatin clinical trials, however significant decreases in circulating ubiquinone levels in patients treated with other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure. Lipoprotein A In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein(a) [Lp(a)] concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high-risk patients placed on rosuvastatin therapy. Further studies have demonstrated statins affect Lp(a) levels differently in patients with dyslipidemia depending on their apo(a) phenotype; statins increase Lp(a) levels exclusively in patients with the low molecular weight apo(a) phenotype. 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 Rosuvastatin is that it Rosuvastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Rosuvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Rosuvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL. In vitro and in vivo animal studies also demonstrate that rosuvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation. Rosuvastatin exerts an anti-inflammatory effect on rat mesenteric microvascular endothelium by attenuating leukocyte rolling, adherence and transmigration. The drug also modulates nitric oxide synthase (NOS) expression and reduces ischemic-reperfusion injuries in rat hearts. Rosuvastatin increases the bioavailability of nitric oxide by upregulating NOS and by increasing the stability of NOS through post-transcriptional polyadenylation. It is unclear as to how rosuvastatin brings about these effects though they may be due to decreased concentrations of mevalonic acid. 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. Rosuvastatin absorption: In a study of healthy white male volunteers, the absolute oral bioavailability of rosuvastatin was found to be approximately 20% while absorption was estimated to be 50%, which is consistent with a substantial first-pass effect after oral dosing. Another study in healthy volunteers found that the peak plasma concentration (Cmax) of rosuvastatin was 6. 06ng/mL and was reached at a median of 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to dose. Neither food nor evening versus morning administration was shown to have an effect on the AUC of rosuvastatin. Many statins are known to interact with hepatic uptake transporters and thus reach high concentrations at their site of action in the liver. Breast Cancer Resistance Protein (BCRP) is a membrane-bound protein that plays an important role in the absorption of rosuvastatin, particularly as CYP3A4 has minimal involvement in its metabolism. Evidence from pharmacogenetic studies of c. 421C>A single nucleotide polymorphisms (SNPs) in the gene for BCRP has demonstrated that individuals with the 421AA genotype have reduced functional activity and 2. 4-fold higher AUC and Cmax values for rosuvastatin compared to study individuals with the control 421CC genotype. This has important implications for the variation in response to the drug in terms of efficacy and toxicity, particularly as the BCRP c. 421C>A polymorphism occurs more frequently in Asian populations than in Caucasians. Other statin drugs impacted by this polymorphism include fluvastatin and atorvastatin. Genetic differences in the OATP1B1 (organic-anion-transporting polypeptide 1B1) hepatic transporter have also been shown to impact rosuvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c. 521T>C SNP showed that rosuvastatin AUC was increased 1. 62-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. Other statin drugs impacted by this polymorphism include simvastatin, pitavastatin, atorvastatin, and pravastatin. For patients known to have the above-mentioned c. 421AA BCRP or c. 521CC OATP1B1 genotypes, a maximum daily dose of 20mg of rosuvastatin is recommended to avoid adverse effects from the increased exposure to the drug, such as muscle pain and risk of rhabdomyolysis. 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 Rosuvastatin is Rosuvastatin undergoes first-pass extraction in the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The mean volume of distribution at steady-state of rosuvastatin is approximately 134 litres. 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. Rosuvastatin is Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations. 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. Rosuvastatin metabolism: Rosuvastatin is not extensively metabolized, as demonstrated by the small amount of radiolabeled dose that is recovered as a metabolite (~10%). Cytochrome P450 (CYP) 2C9 is primarily responsible for the formation of rosuvastatin's major metabolite, N-desmethylrosuvastatin, which has approximately 20-50% of the pharmacological activity of its parent compound in vitro. However, this metabolic pathway isn't deemed to be clinically significant as there were no observable effects found on rosuvastatin pharmacokinetics when rosuvastatin was coadministered with fluconazole, a potent CYP2C9 inhibitor. In vitro and in vivo data indicate that rosuvastatin has no clinically significant cytochrome P450 interactions (as substrate, inhibitor or inducer). Consequently, there is little potential for drug-drug interactions upon coadministration with agents that are metabolized by cytochrome P450. 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. Rosuvastatin is eliminated via Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route. A study in healthy adult male volunteers found that approximately 90% of the rosuvastatin dose was recovered in feces within 72 hours after dose, while the remaining 10% was recovered in urine. The drug was completely excreted from the body after 10 days of dosing. They also found that approximately 76. 8% of the excreted dose was unchanged from the parent compound, with the remaining dose recovered as the metabolites n-desmethyl rosuvastatin and rosuvastatin-5S-lactone. Renal tubular secretion is responsible for >90% of total renal clearance, and is believed to be mediated primarily by the uptake transporter OAT3 (Organic anion transporter 1), while OAT1 had minimal involvement. 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 Rosuvastatin is The elimination half-life (t½) of rosuvastatin is approximately 19 hours and does not increase with increasing doses. The clearance of Abrocitinib is There is no information available. No clearance information is available for Rosuvastatin. 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. Rosuvastatin toxicity includes Generally well-tolerated. Side effects may include myalgia, constipation, asthenia, abdominal pain, and nausea. Other possible side effects include myotoxicity (myopathy, myositis, rhabdomyolysis) and hepatotoxicity. To avoid toxicity in Asian patients, lower doses should be considered. Pharmacokinetic studies show an approximately two-fold increase in peak plasma concentration and AUC in Asian patients (Philippino, Chinese, Japanese, Korean, Vietnamese, or Asian-Indian descent) compared to Caucasian patients. Brand names of Abrocitinib include No brand names available. Brand names of Rosuvastatin include Crestor, Ezallor, Roszet. No synonyms are available for Abrocitinib. No synonyms are available for Rosuvastatin. Rosuvastatina Abrocitinib summary: It is Abrocitinib is a kinase inhibitor used to treat moderate-to-severe atopic dermatitis in adults. Rosuvastatin summary: It is Rosuvastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and reduce the risk of cardiovascular disease including myocardial infarction and stroke. Answer: Both of these agents are reported to be metabolized by CYP2C9. Concomitant administration of multiple CYP2C9 substrates can result in competition for the CYP2C9 binding sites and consequently reduced metabolism and increased plasma levels of one or both of the affected drugs. Elevated plasma levels may result in a higher incidence and/or severity of adverse effects.

Abrocitinib

Drug A is Bupivacaine. Drug B is Cisapride. The severity of the interaction is major. The metabolism of Bupivacaine can be decreased when combined with Cisapride. 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. 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. Cisapride is indicated for the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease. 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. Cisapride pharmacodynamics: Cisapride is a parasympathomimetic which acts as a serotonin 5-HT 4 agonist; upon activation of the receptor signaling pathway, cisapride promotes the release of acetylcholine neurotransmitters in the enteric nervous system. Cisapride stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Cisapride increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder. Cisapride does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity. 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 Cisapride is that it Cisapride acts through the stimulation of the serotonin 5-HT 4 receptors which increases acetylcholine release in the enteric nervous system (specifically the myenteric plexus). This results in increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and the duodenal bulb, and increased peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. 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. Cisapride absorption: Cisapride is rapidly absorbed after oral administration, with an absolute bioavailability of 35-40%. No volume of distribution information is available for Bupivacaine. No volume of distribution information is available for Cisapride. Bupivacaine is Bupivacaine is ~95% protein bound. bound to plasma proteins. Cisapride is 97. 5% 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. Cisapride metabolism: Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme. Bupivacaine is eliminated via Only 6% of bupivacaine is excreted unchanged in the urine. Cisapride is eliminated via No route of elimination available. 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 Cisapride is 6-12 hours. No clearance information is available for Bupivacaine. No clearance information is available for Cisapride. 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. No toxicity information is available for Cisapride. 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 Cisapride include No brand names available. No synonyms are available for Bupivacaine. Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine No synonyms are available for Cisapride. Bupivacaine summary: It is Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures. Cisapride summary: It is Cisapride is a medication used to treat heartburn associated with GERD. 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.

Bupivacaine

Drug A is Brodalumab. Drug B is Raxibacumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Raxibacumab is combined with Brodalumab. 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. Brodalumab is indicated for Brodalumab has been approved for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. Raxibacumab is indicated for Raxibacumab is indicated for the treatment of adult and pediatric patients with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs, and for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate. Brodalumab pharmacodynamics: Increase in the level of IL-17 due to blocking of its receptors. Raxibacumab pharmacodynamics: No pharmacodynamics available. The mechanism of action of Brodalumab is that it Brodalumab binds with high affinity to interleukin (IL)-17 receptor A, thereby inhibiting several pro-inflammatory cytokines from the IL-17 family. The mechanism of action of Raxibacumab is that it Raxibacumab is a monoclonal antibody that binds free PA with an affinity equilibrium dissociation constant (Kd) of 2. 78 ± 0. 9 nM. Raxibacumab inhibits the binding of PA to its cellular receptors, preventing the intracellular entry of the anthrax lethal factor and edema factor, the enzymatic toxin components responsible for the pathogenic effects of anthrax toxin. It does not have direct antibacterial activity. No absorption information is available for Brodalumab. Raxibacumab absorption: Raxibacumab does not cross the blood-brain-barrier. When a single IV dose of 40 mg/kg was administered to healthy, male and female human subjects, the pharmacokinetic parameters are as follows:. Cmax = 1020. 3 ± 140. 6 mcg/mL; AUCinf = 15845. 8 ± 4333. 5 mcg·day/mL. Bioavailability is also dependent on site of injection. When administered to the vastus lateralis, the bioavailability is 71-85%. When administered to the gluteus maximus, the bioavailability is 50-54%. The volume of distribution of Brodalumab is 4. 62 L. The volume of distribution of Raxibacumab is Steady state volume of distribution exceeded plasma volume. This suggests that there is some distribution into the tissues. No protein binding information is available for Brodalumab. No protein binding information is available for Raxibacumab. No metabolism information is available for Brodalumab. No metabolism information is available for Raxibacumab. Brodalumab is eliminated via No route of elimination available. Raxibacumab is eliminated via No route of elimination available. The half-life of Brodalumab is No half-life available. The half-life of Raxibacumab is Mean terminal elimination half-lives of raxibacumab are as follows:. IM dose = 15-19 days; IV dose = 16-19 days The clearance of Brodalumab is 0. 223 L/day. The clearance of Raxibacumab is Clearance values were much smaller than the glomerular filtration rate indicating that there is virtually no renal clearance of raxibacumab. No toxicity information is available for Brodalumab. Raxibacumab toxicity includes The most frequently reported adverse reactions were rash, pain in extremity, pruritus, and somnolence. Brand names of Brodalumab include Siliq. Brand names of Raxibacumab include No brand names available. No synonyms are available for Brodalumab. No synonyms are available for Raxibacumab. Brodalumab summary: It is Brodalumab is a monoclonal antibody used to treat moderate to severe plaque psoriasis. Raxibacumab summary: It is Raxibacumab is a monoclonal antibody used in conjunction with an antibacterial regimen to treat patients with inhalational anthrax caused by Bacillus anthracis and for prophylaxis of inhalational anthrax when appropriate. 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.

Brodalumab

Drug A is Antilymphocyte immunoglobulin (horse). Drug B is Bexarotene. The severity of the interaction is major. The risk or severity of adverse effects can be increased when Bexarotene is combined with Antilymphocyte immunoglobulin (horse). Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. Antilymphocyte immunoglobulin (horse) is indicated for prevention of renal transplant rejection and for the treatment of aplastic anemia. Bexarotene is indicated for Used orally for the treatment of skin manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy. Also used topically for the treatment of skin lesions in early (stage IA and IB) CTCL in patients who experience refractory or persistent disease with the use of other therapies or are intolerant of other therapies. Antilymphocyte immunoglobulin (horse) pharmacodynamics: No pharmacodynamics available. Bexarotene pharmacodynamics: Bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). Bexarotene is indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. Bexarotene selectively binds and activates retinoid X receptor subtypes (RXR α, RXR β, RXR γ ). RXRs can form heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models. The mechanism of action of Antilymphocyte immunoglobulin (horse) is that it No mechanism of action available. The mechanism of action of Bexarotene is that it Bexarotene selectively binds with and activates retinoid X receptor subtypes. There are three subtypes in total: RXR α, RXR β, RXR γ. The exact mechanism of action of bexarotene in the treatment of CTCL is unknown but the drug has activity in all clinical stages of CTCL. No absorption information is available for Antilymphocyte immunoglobulin (horse). No absorption information is available for Bexarotene. The volume of distribution of Antilymphocyte immunoglobulin (horse) is During infusion of 10 to 15 mg/kg/day, the mean peak value (n = 27 renal transplant patients) was found to be 727 ± 310 μg/mL. No volume of distribution information is available for Bexarotene. No protein binding information is available for Antilymphocyte immunoglobulin (horse). Bexarotene is >99% bound to plasma proteins. No metabolism information is available for Antilymphocyte immunoglobulin (horse). No metabolism information is available for Bexarotene. Antilymphocyte immunoglobulin (horse) is eliminated via No route of elimination available. Bexarotene is eliminated via Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of administered dose). The half-life of Antilymphocyte immunoglobulin (horse) is The half-life of equine immunoglobulin after ATGAM infusion was found to be 5. 7 ± 3. 0 days in one group of recipients. The range for half-life was 1. 5 to 13 days. The half-life of Bexarotene is 7 hours. No clearance information is available for Antilymphocyte immunoglobulin (horse). No clearance information is available for Bexarotene. Antilymphocyte immunoglobulin (horse) toxicity includes The most commonly reported adverse reactions (occurring in greater than 10% of patients) are pyrexia, chills, rash, thrombocytopenia, leukopenia and arthralgia. No toxicity information is available for Bexarotene. Brand names of Antilymphocyte immunoglobulin (horse) include Atgam. Brand names of Bexarotene include Targretin. No synonyms are available for Antilymphocyte immunoglobulin (horse). No synonyms are available for Bexarotene. Bexarotène Bexarotene Bexaroteno Bexarotenum Antilymphocyte immunoglobulin (horse) summary: It is Antilymphocyte immunoglobulin (horse) is a primarily IgG immune globulin used to manage allograft rejection in renal transplant patients. Bexarotene summary: It is Bexarotene is a retinoid drug used for cutaneous manifestations of T-cell lymphoma in patients who have not responded well to previous systemic therapy. Answer: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression.

Antilymphocyte immunoglobulin (horse)

Drug A is Ranibizumab. Drug B is Trastuzumab deruxtecan. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Ranibizumab is combined with Trastuzumab deruxtecan. 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. 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. Trastuzumab deruxtecan is indicated for In the US, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. It is also indicated to treat adults with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Trastuzumab deruxtecan is also indicated to treat adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. In Canada, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously been treated with trastuzumab emtansine, or who have received at least one prior anti-HER2-based regimen either in the metastatic setting or in the adjuvant/neoadjuvant setting who have experienced disease recurrence during or within 6 months of adjuvant/neoadjuvant therapy. Trastuzumab deruxtecan is also indicated in Canada for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received at least one prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. In Europe, trastuzumab deruxtecan is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens and unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. It is also indicated for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. It is also indicated as a monotherapy for the treatment of adult patients with advanced non-small cell lung cancer whose tumors have an activating HER2 mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy. 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. Trastuzumab deruxtecan pharmacodynamics: Trastuzumab demonstrates antitumor activity against certain types of HER2 positive breast cancer, however, clinical trials are still ongoing to confirm its efficacy. By exploiting both targeted antibody and cytotoxic effects, trastuzumab deruxtecan can effectively destroy tumors. The FDA label warns of a potential risk for neutropenia, interstitial lung disease/pneumonitis, and left ventricular dysfunction following the use of this drug. 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. The mechanism of action of Trastuzumab deruxtecan is that it Trastuzumab deruxtecan is a humanized anti-HER2 IgG1 antibody, targeting cancer cause by mutation of the HER2 gene. In addition, the small molecule portion of this drug, deruxtecan (DXd), is a topoisomerase I inhibitor. It is attached to the antibody by a peptide linker. After trastuzumab deruxtecan binds to HER2 found on malignant cells, it is internalized and linker cleavage occurs through the actions of lysosomal enzymes. After it is released through cleavage, DXd causes targeted DNA damage and apoptosis in cancer cells, due to the ability to cross cell membranes. Normally, drugs in this class (antibody-drug conjugates) present a challenge. The monoclonal antibody accurately targets cancer cells, however exert limited killing action. The addition of a cytotoxic agent (a topoisomerase I inhibitor in this case) effectively kills dividing cancer cells, including those in the healthy tissues, leading to various adverse effects. The peptide linker used to formulate this drug is cleavable, which is unique to other antibody-drug conjugates, allowing for increased efficacy and reduced drug resistance to topoisomerase. 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. Trastuzumab deruxtecan absorption: The Cmax of trastuzumab deruxtecan at normal therapeutic doses was 122 μg/mL (20%). The AUC of trastuzumab deruxtecan was 735 μg·day/mL (31%). 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. The volume of distribution of Trastuzumab deruxtecan is The estimated volume of distribution of trastuzumab deruxtecan in the central compartment is 2. 77 L, according to a population based pharmacokinetic study. Pharmacokinetic studies found that the unchanged drug is distributed in the blood and is not significantly retained in tissues. Ranibizumab is There is no information available. bound to plasma proteins. Trastuzumab deruxtecan is The Dxd portion of the drug has a plasma protein binding estimated at 97%. bound to plasma proteins. Ranibizumab metabolism: The metabolism of ranibizumab has not been studied. Since it is a monoclonal antibody fragment, ranibizumab is expected to undergo catabolism. Trastuzumab deruxtecan metabolism: Trastuzumab deruxtecan is likely broken down into small peptides and amino acids through catabolism, just as the metabolism of endogenous IgG. Cathepsin B and L enzymes are thought to be involved in the cleavage of the peptide linker that joins the topoisomerase I inhibitor and the antibody. In vitro, DXd, the topoisomerase inhibitor portion of the drug, is found to be metabolized by CYP3A4. Ranibizumab is eliminated via There is no information available. Trastuzumab deruxtecan is eliminated via A pharmacokinetic study revealed that this drug was mainly excreted in the feces. Another study determined that 67% of a dose was excreted in the feces. Unmetabolized DXd was found in the urine during a pharmacokinetic study. 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 half-life of Trastuzumab deruxtecan is In a pharmacokinetic study, the median elimination half-life of trastuzumab deruxtecan was about 5. 8 days. 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. The clearance of Trastuzumab deruxtecan is Trastuzumab deruxtecan is rapidly cleared from systemic circulation. Estimated systemic clearance of trastuzumab deruxtecan is 0. 42 L/day, according to a population pharmacokinetic analysis. DXd showed a systemic clearance of about 19. 2 L/h. 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. Trastuzumab deruxtecan toxicity includes LD50 and overdose information are not currently available, but effects of an overdose are likely to impact the lungs, heart, and circulatory system, leading to significant toxicity. Brand names of Ranibizumab include Byooviz, Cimerli, Lucentis, Susvimo. Brand names of Trastuzumab deruxtecan include Enhertu. No synonyms are available for Ranibizumab. No synonyms are available for Trastuzumab deruxtecan. 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. Trastuzumab deruxtecan summary: It is Trastuzumab deruxtecan is an antibody used to treat certain types of unresectable or metastatic HER2 positive breast 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.

Ranibizumab

Drug A is Adalimumab. Drug B is Esmolol. The severity of the interaction is moderate. The metabolism of Esmolol 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 CYP2D6 substrates. 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. Esmolol is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Also used in noncompensatory sinus tachycardia where the rapid heart rate requires specific intervention. 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. Esmolol pharmacodynamics: No pharmacodynamics available. 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 Esmolol is that it Similar to other beta-blockers, esmolol blocks the agonistic effect of the sympathetic neurotransmitters by competing for receptor binding sites. Because it predominantly blocks the beta-1 receptors in cardiac tissue, it is said to be cardioselective. In general, so-called cardioselective beta-blockers are relatively cardioselective; at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases. At therapeutic dosages, esmolol does not have intrinsic sympathomimetic activity (ISA) or membrane-stabilizing (quinidine-like) activity. Antiarrhythmic activity is due to blockade of adrenergic stimulation of cardiac pacemaker potentials. In the Vaughan Williams classification of antiarrhythmics, beta-blockers are considered to be class II agents. 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. Esmolol absorption: Rapidly absorbed, steady-state blood levels for dosages from 50-300 µg/kg/min (0. 05-0. 3 mg/kg/mm) are obtained within five minutes. 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 volume of distribution information is available for Esmolol. No protein binding information is available for Adalimumab. Esmolol is 55% bound to human plasma protein, while the acid metabolite is 10% bound. bound to plasma proteins. No metabolism information is available for Adalimumab. Esmolol metabolism: Esmolol undergoes rapid hydrolysis of ester linkage which is catalyzed by esterases found in the cytosol of red blood cells (RBCs). The plasma cholinersterases or RBC membrane acetylcholinesterases are not involved in this metabolic reaction. Metabolism of the drug occurs mainly in RBCs to form a free acid metabolite (with 1/1500 the activity of esmolol) and methanol. Adalimumab is eliminated via Adalimumab is most likely removed by opsonization via the reticuloendothelial system. Esmolol is eliminated via Consistent with the high rate of blood-based metabolism of esmolol hydrochloride, less than 2% of the drug is excreted unchanged in the urine. The acid metabolite has an elimination half-life of about 3. 7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. Excretion of the acid metabolite is significantly decreased in patients with renal disease, with the elimination half-life increased to about ten-fold that of normals, and plasma levels considerably elevated. 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 Esmolol is Rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. The acid metabolite has an elimination half-life of about 3. 7 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 Esmolol is 20 L/kg/hr [Men]. 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. Esmolol toxicity includes Symptoms of overdose include cardiac arrest, bradycardia, hypotension, electromechanical dissociation and loss of consciousness. Brand names of Adalimumab include Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry. Brand names of Esmolol include Brevibloc. No synonyms are available for Adalimumab. No synonyms are available for Esmolol. 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. Esmolol summary: It is Esmolol is a cardioselective beta-adrenergic blocker used for the short-term control of ventricular rate and heart rate in various types of tachycardia, including perioperative tachycardia and hypertension. 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 CYP2D6 substrates.

Adalimumab

Drug A is Bromocriptine. Drug B is Triptorelin. The severity of the interaction is moderate. The therapeutic efficacy of Bromocriptine can be decreased when used in combination with Triptorelin. 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. 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. Triptorelin is indicated for Triptorelin is indicated for the palliative treatment of advanced prostate cancer. 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. Triptorelin pharmacodynamics: The first administration of triptorelin is followed by a transient surge of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol,and testosterone. The time, peak and decline of testosterone in the body varies depending on the dose administered. This initial surge is often responsible for worsening of prostate cancer symptoms such as urethral or bladder outlet obstruction, bone pain, spinal cord injury and hematuria in the early stages. A sustained decrease in FSH and LH, and significant reduction of testicular steroidogenesis is usually seen 2-4 weeks post-initiation of therapy. This result is a reduction of serum testosterone to levels which are typically seen in surgically castrated men. Ultimately, tissues and functions that require these hormones become inactive. The effects of triptorelin can usually be reversed once the drug is discontinued. 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 Triptorelin is that it Triptorelin is a synthetic agonist analog of gonadotropin releasing hormone (GnRH). Animal studies comparing triptorelin to native GnRH found that triptorelin had 13 fold higher releasing activity for luteinizing hormone, and 21-fold higher releasing activity for follicle-stimulating hormone. 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. Triptorelin absorption: Following IV administration of triptorelin, triptorelin is completely absorbed. No volume of distribution information is available for Bromocriptine. The volume of distribution of Triptorelin is After a single IV dose of 0. 5mg, the volume of distribution of triptorelin peptide in healthy males was 30 - 33L. Bromocriptine is 90-96% bound to serum albumin bound to plasma proteins. Triptorelin is Triptorelin does not bind to plasma proteins at clinically relevant concentrations. 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. Triptorelin metabolism: The metabolism of triptorelin in humans is not well understood; however, metabolism likely does not involve hepatic enzymes such as cytochrome P450. Whether or not triptorelin affects, or how it affects other metabolizing enzymes is also poorly understood. Triptorelin has no identified metabolites. Bromocriptine is eliminated via Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. Triptorelin is eliminated via Elimination of triptorelin involves both the kidneys and the liver. The half-life of Bromocriptine is 2-8 hours. The half-life of Triptorelin is The pharmacokinetics of triptorelin follows a 3 compartment model. The half lives are estimated to be 6 minutes, 45 minutes, and 3 hours respectively. No clearance information is available for Bromocriptine. The clearance of Triptorelin is In healthy male volunteers, total clearance of triptorelin was 211. 9 mL/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. Triptorelin toxicity includes Some of the most commonly reported adverse effects of triptorelin are hot flushes reported in 58. 6% of patients, skeletal pain in 12. 1%, impotence in 7. 1%, and headache in 5. 0%. Other reported adverse effects include injection site pain, general body pain, leg pain, fatigue, hypertension, dizziness, diarrhea, vomiting, insomnia, emotional lability, anemia, pruritus, urinary tract infections, and urinary retention. Triptorelin is classified as Pregnancy Category X and contraindicated in pregnant women or in women who may become pregnant. Hormonal changes caused by triptorelin increase the risk for pregnancy loss. Studies done on pregnant rats demonstrated maternal toxicity and embryo-fetal toxicities. Brand names of Bromocriptine include Cycloset, Parlodel. Brand names of Triptorelin include Decapeptyl, Trelstar, Triptodur. No synonyms are available for Bromocriptine. Bromocriptine Bromocriptinum Bromocryptine Bromoergocriptine Bromoergocryptine No synonyms are available for Triptorelin. Triptorelina Triptoreline Triptorelinum 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. Triptorelin summary: It is Triptorelin is a GnRH agonist indicated for the palliative treatment of advanced prostate cancer. 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.

Bromocriptine

Drug A is Abatacept. Drug B is Flunarizine. The severity of the interaction is moderate. The metabolism of Flunarizine 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 CYP1A2 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. 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. 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. Flunarizine pharmacodynamics: Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. 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 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. 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%. Flunarizine absorption: 85% following oral administration. 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 Flunarizine. No protein binding information is available for Abatacept. Flunarizine is 99% bound to plasma proteins bound to plasma proteins. No metabolism information is available for Abatacept. Flunarizine metabolism: Hepatic, to two metabolites via N-dealylation and hydroxylation. Abatacept is eliminated via Kidney and liver. Flunarizine is eliminated via No route of elimination available. 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 Flunarizine is 18 days. 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 Flunarizine. 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. 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 Abatacept include Orencia. Brand names of Flunarizine include No brand names available. No synonyms are available for Abatacept. No synonyms are available for Flunarizine. Flunarizine Flunarizinum 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. 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 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.

Abatacept

Drug A is Abacavir. Drug B is Rasagiline. The severity of the interaction is minor. Abacavir may decrease the excretion rate of Rasagiline 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. Rasagiline is indicated for the treatment of the signs and symptoms of idiopathic Parkinsons disease as initial monotherapy and as adjunct therapy to levodopa. 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. Rasagiline pharmacodynamics: Rasagiline is a propargylamine and an irreversible inhibitor of monoamine oxidase (MAO). MAO, a flavin-containing enzyme, regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. It is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO-A is found predominantly in the GI tract and liver, and regulates the metabolic degradation of circulating catecholamines and dietary amines. MAO-B is the major form in the human brain and is responsible for the regulation of the metabolic degradation of dopamine and phenylethylamine. In ex vivo animal studies in brain, liver and intestinal tissues rasagiline was shown to be a potent,selective, and irreversible monoamine oxidase type B (MAO-B) inhibitor. At the recommended therapeutic doses, Rasagiline was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The selectivity of rasagiline for inhibiting only MAO-B (and not MAO-A) in humans and the sensitivity to tyramine during rasagiline treatment at any dose has not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications. 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 Rasagiline is that it The precise mechanisms of action of rasagiline is unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction. 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. Rasagiline absorption: Rasagiline is rapidly absorbed following oral administration. The absolute bioavailability of rasagiline is about 36%. The volume of distribution of Abacavir is 0. 86 ± 0. 15 L/kg [IV administration]. The volume of distribution of Rasagiline is 87 L. Abacavir is Moderate (approximately 50%). Binding of abacavir to plasma protein was independent of concentration. bound to plasma proteins. Rasagiline is Plasma protein binding ranges from 88-94% with mean extent of binding of 61-63% to human albumin over the concentration range of 1-100 ng/ml. 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. Rasagiline metabolism: Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism. 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. Rasagiline is eliminated via Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine. The half-life of Abacavir is 1. 54 ± 0. 63 hours. The half-life of Rasagiline is Rasagiline has a mean steady-state half life of 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B. 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 Rasagiline. 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). Rasagiline toxicity includes Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. Brand names of Abacavir include Epzicom, Kivexa, Triumeq, Trizivir, Ziagen. Brand names of Rasagiline include Azilect. No synonyms are available for Abacavir. ABC No synonyms are available for Rasagiline. Rasagiline Abacavir summary: It is Abacavir is an antiviral nucleoside reverse transcriptase inhibitor used in combination with other antiretrovirals for the treatment of HIV. Rasagiline summary: It is Rasagiline is an irreversible inhibitor of monoamine oxidase used for the symptomatic management of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa. 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 Anthrax immune globulin human. Drug B is Diroximel fumarate. The severity of the interaction is moderate. The therapeutic efficacy of Anthrax immune globulin human can be decreased when used in combination with Diroximel fumarate. 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. Anthrax immune globulin human is indicated for Anthrax immune globulin is indicated for the treatment of inhalational anthrax in adult and pediatric patients in combination with appropriate antibacterial drugs. Diroximel fumarate is indicated for Diroximel fumarate is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults; specifically active secondary progressive disease and clinically isolated syndrome, as well as relapsing-remitting MS. Anthrax immune globulin human pharmacodynamics: No pharmacodynamics available. Diroximel fumarate pharmacodynamics: Diroximel fumarate relieves the neurological symptoms of relapsing MS with less gastrointestinal effects than its bioequivalent counterpart, dimethyl fumarate. It is important to note that diroximel fumarate can cause angioedema, anaphylaxis, hepatotoxicity, flushing, lymphopenia, and Progressive Multifocal Leukoencephalopathy (PML). Discontinue diroximel fumarate immediately if PML is suspected or if anaphylaxis or angioedema occur. Liver function and total bilirubin should be tested prior to initiating diroximel fumarate and during treatment. A complete blood count (CBC) should be obtained prior to starting diroximel fumarate, after the first 6 months of administration, and at subsequent intervals of 6 to 12 months following this period. Suspend treatment if lymphocyte counts are measured to be less than 0. 5 × 109/L for more than 6 months. The mechanism of action of Anthrax immune globulin human is that it Polyclonal anthrax immune globulin is a passive immunizing agent that neutralizes anthrax toxin by binding to Protective Antigen (PA) to prevent PA-mediated cellular entry of anthrax edema factor and lethal factor. It is administered in combination with appropriate antibiotic therapy as the immunoglobulin itself is not known to have direct antibacterial activity against anthrax bacteria, which otherwise may continue to grow and produce anthrax toxins. The mechanism of action of Diroximel fumarate is that it Currently, the mechanism of action of this drug in MS is not fully understood. Diroximel fumarate is hypothesized to regulate cell signaling pathways, causing beneficial immune and neuroprotective effects. Monomethyl fumarate (MMF) is the active metabolite of diroximel fumarate, and activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in humans. This pathway occurs as a response to oxidative stress in cells. In addition to the above, MMF is a nicotinic acid receptor agonist in the laboratory setting. The relevance of this finding to the treatment of MS is unknown at this time. The mechanism by which this drug leads to less gastrointestinal effects is purported to be due to its lack of a methanol leaving group in its chemical structure, and substitution with inert 2-hydroxyethyl succinimide. Anthrax immune globulin human absorption: Peak levels were reached immediately after infusion and then declined over the duration of study (84 days). Mean activity remained above the lower limit of quantitation (5 milliunits per mL) over the entire 84-day post-dose period for the three doses studied. Cmax was found to be 83. 0 mU/mL while Tmax was found to be 0. 116 days. Diroximel fumarate absorption: Diroximel fumarate is rapidly absorbed in the gastrointestinal tract following administration, like its bioequivalent drug, dimethyl fumarate. The median Tmax of monomethyl fumarate (MMF) after oral administration ranges from 2. 5-3 hours with a mean Cmax of 2. 11 mg/L. The bioequivalent drug, dimethyl fumarate, administered to healthy volunteers also shows a similar mean Tmax and Cmax. The average steady state concentration of this metabolite is estimated at 8. 32 mg. hr/L after it is administered twice a day in patients with MS. The mean AUC0–∞ of the active metabolite is 88mg × min L−1. Food appears to significantly reduce the Cmax of diroximel fumarate's active metabolite, MMF, when compared to administration in the fasted state. The volume of distribution of Anthrax immune globulin human is 5714. 8 mL. The volume of distribution of Diroximel fumarate is The apparent volume of distribution ranges from 72L to 83L. Monomethyl fumarate (MMF), the active metabolite of diroximel fumarate, crosses the blood brain barrier. No protein binding information is available for Anthrax immune globulin human. Diroximel fumarate is Plasma protein binding of MMF, the active metabolite of diroximel fumarate, ranges from 27-45%. bound to plasma proteins. No metabolism information is available for Anthrax immune globulin human. Diroximel fumarate metabolism: Esterases heavily metabolize diroximel fumarate, as well as its bioequivalent drug, dimethyl fumarate, in the liver. These enzymes are present in high quantities in the gastrointestinal tract, tissues, and blood. Esterase metabolism of this drug produces the active metabolite, mono methyl fumarate (MMF), before it moves to the systemic circulation. In addition, the major inactive metabolite, 2-hydroxyethyl succinimide (HES) is produced along with small amounts of methanol, and another inactive metabolite, RDC-8439. Following esterase metabolism, the tricarboxylic acid (TCA)cycle further metabolizes MMF. The major metabolites of MMF in plasma include fumaric acid, citric acid, and glucose. It is important that methanol is a major metabolite of dimethyl fumarate metabolism, but a minor metabolite of diroximel fumarate metabolism, conferring its lower risk of gastrointestinal effects. Anthrax immune globulin human is eliminated via No route of elimination available. Diroximel fumarate is eliminated via Monomethyl fumarate is eliminated as carbon dioxide through expired breath. Negligible amounts, under 0. 3% of the ingested dose, are measured in urine. The inactive metabolite, 2-hydroxyethyl succinimide (HES), representing 58-63% of the ingested dose, is excreted in urine. The half-life of Anthrax immune globulin human is 24. 3 days. The half-life of Diroximel fumarate is The terminal half-life of monomethyl fumarate (MMF), diroximel fumarate's active metabolite, is estimated to be 1 hour. The clearance of Anthrax immune globulin human is 174. 2 mL/day. The clearance of Diroximel fumarate is No clearance information is available on the FDA label for diroximel fumarate, however, clinical study results for its active metabolite, monomethyl fumarate show a mean apparent total clearance from the plasma after oral administration of 1. 54 mgL−1. Anthrax immune globulin human toxicity includes The most common adverse reactions to Anthrasil observed in >5% of healthy volunteers in clinical trials were headache, infusion site pain and swelling, nausea, and back pain. Diroximel fumarate toxicity includes Currently, an MSDS for diroximel fumarate is unavailable. The MSDS for its bioequivalent counterpart, dimethyl fumarate, indicates an oral LD50 of 2,240 mg/kg in rats. There is no information regarding overdose on the FDA label for diroximel fumarate. Cases of overdose with its bioequivalent counterpart, dimethyl fumarate, have been reported in the literature, and symptoms reflect the adverse effects of this drug. These symptoms include nausea, vomiting, diarrhea, and flushing, among others. Currently there is no antidote to an overdose with diroximel fumarate or dimethyl fumarate. Symptomatic and supportive management are the only options up to this date if an overdose should occur. Brand names of Anthrax immune globulin human include Anthrasil. Brand names of Diroximel fumarate include Vumerity. No synonyms are available for Anthrax immune globulin human. No synonyms are available for Diroximel fumarate. Anthrax immune globulin human summary: It is Anthrax immune globulin human is an immunizing agent used for the treatment of inhalational anthrax in adult and pediatric patients in combination with antibacterial agents. Diroximel fumarate summary: It is Diroximel fumarate is a drug used for the treatment of relapsing forms of Multiple Sclerosis (MS). 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.

Anthrax immune globulin human

Drug A is Bromotheophylline. Drug B is Cinnarizine. The severity of the interaction is moderate. The metabolism of Bromotheophylline can be decreased when combined with Cinnarizine. Due to competition for the CYP1A2 binding sites, substrates of this enzyme may be metabolized at a lower rate. When CYP1A2 substrates are coadministered, this may increase the serum concentration of either or both drug, increasing the risk of toxicity and adverse effects. 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. Cinnarizine is indicated for the treatment of vertigo/meniere's disease, nausea and vomiting, motion sickness and also useful for vestibular symptoms of other origins. 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. Cinnarizine pharmacodynamics: Cinnarizine is an antihistamine and a calcium channel blocker. Histamines mediate a number of activities such as contraction of smooth muscle of the airways and gastrointestinal tract, vasodilatation, cardiac stimulation, secretion of gastric acid, promotion of interleukin release and chemotaxis of eosinophils and mast cells. Competitive antagonists at histamine H1 receptors may be divided into first (sedating) and second (non-sedating) generation agents. Some, such as Cinnarizine also block muscarinic acetylcholine receptors and are used as anti-emetic agents. Cinnarizine through its calcium channel blocking ability also inhibits stimulation of the vestibular system. 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 Cinnarizine is that it Cinnarizine inhibits contractions of vascular smooth muscle cells by blocking L-type and T-type voltage gated calcium channels. Cinnarizine has also been implicated in binding to dopamine D2 receptors, histamine H1 receptors, and muscarinic acetylcholine receptors. 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. No absorption information is available for Cinnarizine. The volume of distribution of Bromotheophylline is This pharmacokinetic property has not been determined. No volume of distribution information is available for Cinnarizine. Bromotheophylline is This pharmacokinetic property has not been determined. bound to plasma proteins. No protein binding information is available for Cinnarizine. Bromotheophylline metabolism: This pharmacokinetic property has not been determined. No metabolism information is available for Cinnarizine. Bromotheophylline is eliminated via This pharmacokinetic property has not been determined. Cinnarizine is eliminated via No route of elimination available. The half-life of Bromotheophylline is The apparent elimination half-life is registered to be 21. 35 hours. The half-life of Cinnarizine is No half-life available. The clearance of Bromotheophylline is This pharmacokinetic property has not been determined. No clearance information is available for Cinnarizine. Bromotheophylline toxicity includes In overdose, bromotheophylline does not produce hepatic toxicity. No toxicity information is available for Cinnarizine. Brand names of Bromotheophylline include Pamprin Multi-symptom, Premsyn Pms. Brand names of Cinnarizine include No brand names available. No synonyms are available for Bromotheophylline. No synonyms are available for Cinnarizine. Cinnarizine Cinnarizinum Bromotheophylline summary: It is No summary available. Cinnarizine summary: It is Cinnarizine is a drug used for the management of labyrinthine disorder symptoms, including vertigo, tinnitus, nystagmus, nausea, and vomiting. Answer: Due to competition for the CYP1A2 binding sites, substrates of this enzyme may be metabolized at a lower rate. When CYP1A2 substrates are coadministered, this may increase the serum concentration of either or both drug, increasing the risk of toxicity and adverse effects.

Bromotheophylline

Drug A is Brentuximab vedotin. Drug B is Levobupivacaine. The severity of the interaction is moderate. The risk or severity of methemoglobinemia can be increased when Brentuximab vedotin is combined with Levobupivacaine. 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. 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. Levobupivacaine is indicated for the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management. 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. Levobupivacaine pharmacodynamics: Levobupivacaine, a local anesthetic agent, is indicated for the production of local or regional anesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures. 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 Levobupivacaine is that it Local anesthetics such as Levobupivacaine block the generation and the 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. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Specifically, the drug binds to the intracellular portion of sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. 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. Levobupivacaine absorption: The plasma concentration of levobupivacaine following therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean Cmax levels of up to 1. 2 µg/mL. 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 Levobupivacaine is 66. 91 ±18. 23 L [after intravenous administration of 40 mg in healthy volunteers]. Brentuximab vedotin is In vitro, the binding of MMAE to human plasma proteins is in the range of 68–82%. bound to plasma proteins. Levobupivacaine is >97% 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. Levobupivacaine metabolism: Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C] levobupivacaine showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+)-bupivacaine was not evident both in vitro and in vivo. 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. Levobupivacaine is eliminated via Following intravenous administration, recovery of the radiolabelled dose of levobupivacaine was essentially quantitative with a mean total of about 95% being recovered in urine and feces in 48 hours. Of this 95%, about 71% was in urine while 24% was in feces. The half-life of Brentuximab vedotin is The terminal half-life is approximately 4-6 days. The half-life of Levobupivacaine is 3. 3 hours. 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 Levobupivacaine is 39. 06 ±13. 29 L/h [after intravenous administration of 40 mg in healthy volunteers]. 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. Levobupivacaine toxicity includes LD50: 5. 1mg/kg in rabbit, intravenous; 18mg/kg in rabbit, oral; 207mg/kg in rabbit, parenteral; 63mg/kg in rat, subcutaneous (Archives Internationales de Pharmacodynamie et de Therapie. Vol. 200, Pg. 359, 1972. ) Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations. Brand names of Brentuximab vedotin include Adcetris. Brand names of Levobupivacaine include No brand names available. No synonyms are available for Brentuximab vedotin. No synonyms are available for Levobupivacaine. Levobupivacaína Levobupivacaine Brentuximab vedotin summary: It is Brentuximab vedotin is a CD30-directed antibody-drug conjugate used to treat various types of lymphoma. Levobupivacaine summary: It is Levobupivacaine is a drug used for nerve block and anesthesia. 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.

Brentuximab vedotin

Drug A is Bupivacaine. Drug B is Sodium ferric gluconate complex. The severity of the interaction is moderate. The risk or severity of hypotension can be increased when Sodium ferric gluconate complex is combined with Bupivacaine. Ferrlecit may cause clinically significant hypotension. 1 Hypotension associated with lightheadedness, malaise, fatigue, weakness or severe pain in the chest, back, flanks, or groin has been reported. These hypotensive reactions may or may not be associated with signs and symptoms of hypersensitivity reactions and usually resolve within one to two hours. Therefore, concomitant use of sodium ferric gluconate complex with hypotensive agents can exacerbate its hypotensive effects. 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. Sodium ferric gluconate complex is indicated for Sodium ferric gluconate complex in sucrose injection is used to deplete the total body content of iron during iron deficiency anemia in patients aged 6 years and older with chronic kidney disease receiving hemodialysis and receiving supplemental epoetin therapy. 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. Sodium ferric gluconate complex pharmacodynamics: Sodium ferric gluconate complex is an exogenous epoetin that acts to restore the body's content of iron, which is essential for normal hemoglobin synthesis, oxygen transport, and enzymatic processes. The complex increases red blood cell production and increased iron utilization. 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 Sodium ferric gluconate complex is that it The complex is endocytosed by macrophages of the reticuloendothelial system. Within an endosome of the macrophage, lysosome fuses with the endosome creating an acidic environment leading to the cleavage of the complex from iron. Iron is then incorporated in ferritin, transferrin or hemoglobin. Sodium ferric gluconate also normalizes RBC production by binding with hemoglobin. 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. Sodium ferric gluconate complex absorption: Peak drug levels (Cmax) varied significantly by dosage and by rate of administration. Highest Cmax value is observed in the regimen in which 125 mg was administered in 7 minutes (19. 0 mg/L). No volume of distribution information is available for Bupivacaine. The volume of distribution of Sodium ferric gluconate complex is Using single-dose pharmacokinetics of either 1. 5 or 3 mg/kg in pediatric patients (mean age 12. 3 ± 2. 5 yr), the volume of distribution was estimated to be 1. 6 ± 0. 6 L. Bupivacaine is Bupivacaine is ~95% protein bound. bound to plasma proteins. Sodium ferric gluconate complex is It is bound to transferrin, ferritin and hemoglobin. 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. No metabolism information is available for Sodium ferric gluconate complex. Bupivacaine is eliminated via Only 6% of bupivacaine is excreted unchanged in the urine. Sodium ferric gluconate complex is eliminated via It is renally eliminated if it is greater than 18,000 Daltons. 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 Sodium ferric gluconate complex is The terminal elimination half-life for drug-bound iron was approximately 1 hour, with the value varying by dose but not by rate of administration. In adults, the shortest terminal elimination half-life of 0. 825h occurs with the 62. 5 mg/4 min dosing regimen and the longest value of 1. 45h is achieved with 125 mg/7 min regimen. In pediatric patients, the half-life was 2 hours following administration of 1. 5 mg/kg dose and 2. 5 hours following administration of 3. 0mg/kg dose. No clearance information is available for Bupivacaine. The clearance of Sodium ferric gluconate complex is Total clearance ranges from 3. 02 to 5. 35 L/h in adult patients. 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. Sodium ferric gluconate complex toxicity includes The Ferrlecit iron complex is not dialyzable. No data is available regarding overdose of Ferrlecit in humans. Excessive dosages of Ferrlecit may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer Ferrlecit to patients with iron overload [see Warnings and Precautions (5. 3)]. Individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events [see Adverse Reactions (6. 2)]. Ferrlecit at elemental iron doses of 125 mg/kg, 78. 8 mg/kg, 62. 5 mg/kg, and 250 mg/kg caused deaths in mice, rats, rabbits, and dogs respectively. The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in respiratory rate, tremors, and convulsions. 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 Sodium ferric gluconate complex include Ferrlecit. No synonyms are available for Bupivacaine. Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine No synonyms are available for Sodium ferric gluconate complex. Bupivacaine summary: It is Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures. Sodium ferric gluconate complex summary: It is Sodium ferric gluconate complex is an iron complex used for the treatment of iron deficiency anemia in adult patients and in pediatric patients age 6 years and older with chronic kidney disease receiving hemodialysis who are receiving supplemental epoetin therapy. Answer: Ferrlecit may cause clinically significant hypotension. 1 Hypotension associated with lightheadedness, malaise, fatigue, weakness or severe pain in the chest, back, flanks, or groin has been reported. These hypotensive reactions may or may not be associated with signs and symptoms of hypersensitivity reactions and usually resolve within one to two hours. Therefore, concomitant use of sodium ferric gluconate complex with hypotensive agents can exacerbate its hypotensive effects.

Bupivacaine

Drug A is Buserelin. Drug B is Fluoxetine. The severity of the interaction is moderate. The risk or severity of QTc prolongation can be increased when Fluoxetine is combined with Buserelin. The risk of QTc prolongation associated with fluoxetine increases in the presence of additional risk factors. 2 It is known that the administration of multiple QTc prolonging agents increases the risk for drug-induced QTc prolongation. Buserelin is indicated for Buserelin may be used in the treatment of hormone-responsive cancers such as prostate cancer or breast cancer, estrogen-dependent conditions (such as endometriosis or uterine fibroids), and in assisted reproduction. Fluoxetine is indicated for Fluoxetine is indicated for both acute and maintenance treatment of major depressive disorder, obsessive compulsive disorder, and bulimia nervosa; however, it is only indicated for acute treatment of panic disorder independent of whether agoraphobia is present. Fluoxetine may also be used in combination with olanzapine to treat depression related to Bipolar I Disorder, and treatment resistant depression. Fluoxetine is additionally indicated for the treatment of female patients with premenstrual dysphoric disorder (PMDD). Buserelin pharmacodynamics: The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on FSH and LH release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH. Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours. Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50-500 mcg SC/day or 300-1200 mcg IN/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis. Fluoxetine pharmacodynamics: Fluoxetine blocks the serotonin reuptake transporter in the presynaptic terminal, which ultimately results in sustained levels of 5-hydroxytryptamine (5-HT) in certain brain areas. However, fluoxetine binds with relatively poor affinity to 5-HT, dopaminergic, adrenergic, cholinergic, muscarinic, and histamine receptors which explains why it has a far more desirable adverse effect profile compared to earlier developed classes of antidepressants such as tricyclic antidepressants. The mechanism of action of Buserelin is that it Buserelin stimulates the pituitary gland's gonadotrophin-releasing hormone receptor (GnRHR). Buserelin desensitizes the GnRH receptor, reducing the amount of gonadotropin. In males, this results in a reduction in the synthesis and release of testosterone. In females, estrogen secretion is inhibited. While initially, there is a rise in FSH and LH levels, chronic administration of Buserelin results in a sustained suppression of these hormones. The mechanism of action of Fluoxetine is that it The monoaminergic hypothesis of depression emerged in 1965 and linked depression with dysfunction of neurotransmitters such as noradrenaline and serotonin. Indeed, low levels of serotonin have been observed in the cerebrospinal fluid of patients diagnosed with depression. As a result of this hypothesis, drugs that modulate levels of serotonin such as fluoxetine were developed. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and as the name suggests, it exerts it's therapeutic effect by inhibiting the presynaptic reuptake of the neurotransmitter serotonin. As a result, levels of 5-hydroxytryptamine (5-HT) are increased in various parts of the brain. Further, fluoxetine has high affinity for 5-HT transporters, weak affinity for noradrenaline transporters and no affinity for dopamine transporters indicating that it is 5-HT selective. Fluoxetine interacts to a degree with the 5-HT 2C receptor and it has been suggested that through this mechanism, it is able to increase noradrenaline and dopamine levels in the prefrontal cortex. Buserelin absorption: Buserelin is water soluble and readily absorbed after subcutaneous injection (70% bioavailable). However, bioavailability after oral absorption. When administered correctly via the nasal route, it may be absorbed in the nasal mucosa to achieve sufficient plasma levels. Fluoxetine absorption: The oral bioavailability of fluoxetine is <90% as a result of hepatic first pass metabolism. In a bioequivalence study, the Cmax of fluoxetine 20 mg for the established reference formulation was 11. 754 ng/mL while the Cmax for the proposed generic formulation was 11. 786 ng/ml. Fluoxetine is very lipophilic and highly plasma protein bound, allowing the drug and it's active metabolite, norfluoxetine, to be distributed to the brain. The volume of distribution of Buserelin is Buserelin circulates in serum predominantly in intact active form. Preferred accumulation is preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. The volume of distribution of Fluoxetine is The volume of distribution of fluoxetine and it's metabolite varies between 20 to 42 L/kg. Buserelin is 15% bound to plasma proteins. Fluoxetine is Approximately 94% of fluoxetine is plasma protein bound. bound to plasma proteins. Buserelin metabolism: It is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal tract. In the pituitary gland, it is inactivated by membrane-located enzymes. Fluoxetine metabolism: Fluoxetine is metabolized to norfluoxetine by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 upon ingestion. Although all of the mentioned enzymes contribute to N-demethylation of fluoxetine, CYP2D6, CYP2C9 and CYP3A4 appear to be the major contributing enzymes for phase I metabolism. In addition, there is evidence to suggest that CYP2C19 and CYP3A4 mediate O-dealkylation of fluoxetine and norfluoxetine to produce para-trifluoromethylphenol which is subsequently metabolized to hippuric acid. Both fluoxetine and norfluoxetine undergo glucuronidation to facilitate excretion. Notably, both the parent drug and active metabolite inhibit CYP2D6 isozymes, and as a result patients who are being treated with fluoxetine are susceptible to drug interactions. Buserelin is eliminated via Buserelin and its inactive metabolites are excreted via the renal and biliary routes. In man it is excreted in urine at 50% in its intact form. Fluoxetine is eliminated via Fluoxetine is primarily eliminated in the urine. The half-life of Buserelin is The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration. The half-life of Fluoxetine is The half life of fluoxetine is significant with the elimination half-life of the parent drug averaging 1-3 days after acute administration, and 4-6 days after chronic administration. Further, the elimination half life of it's active metabolite, norfluoxetine, ranges from 4-16 days after both acute and chronic administration. The half-life of fluoxetine should be considered when switching patients from fluoxetine to another antidepressant since marked accumulation occurs after chronic use. Fluoxetine's long half-life may even be beneficial when discontinuing the drug since the risk of withdrawal is minimized. No clearance information is available for Buserelin. The clearance of Fluoxetine is The clearance value of fluoxetine in healthy patients is reported to be 9. 6 ml/min/kg. Buserelin toxicity includes Buserelin may induce early, transient increase in serum testosterone or estradiol which can lead in the exacerbation of signs and symptoms of metastatic prostate cancer or endometriosis. Adverse reactions reported at more than 10% occurrence include headache, loss of libido in patients with prostate cancer, hot flashes, hypermenorrhea, decreased libido in prostate cancer and endometriosis, flatulence, impotence, vaginal dryness, back pain and nasal mucosa irritation. Fluoxetine toxicity includes In a report that included 234 fluoxetine overdose cases, it was concluded that symptoms resulting from fluoxetine overdose were generally minor and short in duration. The most common overdose adverse effects included drowsiness, tremor, tachycardia, nausea and vomiting, and providing the patient with aggressive supportive care was the recommended intervention. Despite this evidence, more severe adverse effects have been linked to fluoxetine ingestion although most of these reports involved co-ingestion with other substances or drugs as well as other factors. For example, there is a case report that details a patient who ingested 1400 mg of fluoxetine in a suicide attempt and as a result, experienced a generalized seizure three hours later. In a separate case, a 14 year old patient ingested 1. 2 g of fluoxetine and subsequently experienced tonic/clonic seizures, symptoms consistent with serotonin syndrome, and rhabdomyolysis, although the patient did not experience sustained renal injury. Brand names of Buserelin include Suprefact. Brand names of Fluoxetine include Prozac, Sarafem, Symbyax. No synonyms are available for Buserelin. No synonyms are available for Fluoxetine. Fluoxetina Fluoxétine Fluoxetine Fluoxetinum Buserelin summary: It is Buserelin is a LHRH agonist used for the palliative treatment of hormone-dependent advanced carcinoma of the prostate gland in males and treatment of endometriosis in females. Fluoxetine summary: It is Fluoxetine is a selective serotonin reuptake inhibitor used to treat major depressive disorder, bulimia, OCD, premenstrual dysphoric disorder, panic disorder, and bipolar I. Answer: The risk of QTc prolongation associated with fluoxetine increases in the presence of additional risk factors. 2 It is known that the administration of multiple QTc prolonging agents increases the risk for drug-induced QTc prolongation.

Buserelin

Drug A is Corifollitropin alfa. Drug B is Pyrantel. The severity of the interaction is minor. Corifollitropin alfa may decrease the excretion rate of Pyrantel 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. Corifollitropin alfa is indicated for Controlled ovarian stimulation in cases of women who are undergoing fertility treatment to stimulate the development of more than one mature egg simultaneously in the ovaries in combination with a gonadotrophin-releasing hormone (GnRH) antagonist (a type of medicine also used in fertility treatments). Pyrantel is indicated for the treatment of enterobiasis including roundworm (ascariasis), pinworm (enterobius) and hookworm (strongyloides) and hookworm (ancylostoma) in the pyrantel pamoate form. Pyrantel is available in various formulations for humans, dogs, and cats as the pamoate (US Pharmacopeia nomenclature) or embonate (European Pharmacopoeia nomenclature) salt, which contains 34. 7% pyrantel base combined with pamoic acid., . Pyrantel pamoate (embonate) ingested orally is effective for removal and control of ascarid and hookworm infections in puppies and dogs (adult Toxocara canis, Toxascaris leonina, Ancylostoma tubaeforme, An. braziliense, Uncinaria stenocephala), cats (adult Toxocara cati, Toxa. leonina, An. caninum, An. braziliense, U. stenocephala), horses and ponies (adult and immature Parascaris equorum, adult Strongylus vulgaris, S. edentatus, S. equinus, Cyathostomes (Triodontophorus spp., Cyathostomum spp., Cylicodontophorus spp., Cylicocyclus spp., Cylicostephanus spp., Poteriostomum spp. ), Oxyuris equi, Anoplocephala perfoliata), swine (adult Ascaris suum, Oesophagostomum dentatum), and humans (adult A. lumbricoides, Enterobius vermicularis, An. duodenale, Necator americanus). Corifollitropin alfa pharmacodynamics: A single dose of corifollitropin alfa could initiate and sustain multi-follicular growth in patients undergoing controlled ovarian stimulation, such as during in vitro fertilization or intracytoplasmic sperm injection. This drug is structurally similar to follicle stimulating hormone (FSH), a hormone naturally present in females. FSH stimulates the production of eggs (ova) in the ovaries. In corifollitropin alfa, a peptide is attached to the FSH to prolong its activity. As a result, one single dose of the medicine can be administered to stimulate egg production for seven days, replacing daily injections that are normally needed with other FSH medicines. In phase III clinical trials, the number of oocytes retrieved following the administration of corifollitropin alfa was slightly higher compared with the number observed with daily recombinant FSH treatment. Pyrantel pharmacodynamics: It has similar properties to both competitive and depolarizing neuromuscular blocking agents, which leads to the understanding of the paralytic effect of the drug has on parasites, ultimately resulting in the death of the parasite,. The mechanism of action of Corifollitropin alfa is that it Corifollitropin alfa is a long-lasting single injection fusion protein which lacks luteinizing hormone (LH) activity. Only one injection is needed for the first 7 days, which replaces the first 7 daily injections of traditional follicle stimulating hormone (FSH). It is a follicle-stimulation hormone (human α-subunit reduced), a combination of follicle stimulation hormone (human β-subunit reduced) fusion protein with 118-145-chorionic gonadotropin (human β-subunit). Frequent, repetitive injections increase stress and error rates, and are often a burden for women, leading to therapy noncompliance. The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH. Corifollitropin alfa serves as a sustained follicle stimulant that has similar pharmacological effects to recombinant follicle stimulating hormone (rFSH), however, with a relatively long elimination half-life, resulting in a longer duration of action. This is achieved using site-directed mutagenesis and gene transfer techniques to create a glycoprotein that consists of an α-subunit that is identical to human follicle stimulating hormone (FSH) noncovalently bound to a β-subunit comprised of a complete β-chain of human FSH elongated by the carboxyterminal peptide of the β-subunit of human chorionic gonadotrophin (hCG). This unit interacts with the FSH receptor to stimulate the release of oocytes. Corifollitropin alfa does not demonstrate any intrinsic LH/hCG activity. The mechanism of action of Pyrantel is that it By promoting the release of acetylcholine, inhibiting cholinesterase, and stimulating ganglionic neurons, pyrantel serves as a depolarizing neuromuscular blocking agent in helminths. This causes extensive depolarization of the helminth muscle membrane, resulting in tension to the helminth's muscles, leading to paralysis and release of their attachment to the host organism intestinal walls. This action is unlike piperazine, which is a hyperpolarizing neuromuscular blocking agent that causes relaxation of the helminth muscles, leading to a subsequent detachment from the intestinal wall. Excretion of the parasites in the feces occurs by normal peristalsis. Corifollitropin alfa absorption: After one single subcutaneous injection of this drug, the maximal serum concentration is 4. 24 ng/mL (2. 49-7. 21 ng/mL1) and is reached 44 hours (35-57 h) post-dose administration. Its absolute bioavailability is 58% (48-70%). Pyrantel absorption: Pyrantel is poorly absorbed from the GI tract of humans,. Peak serum concentrations occur 1–3 hours after a single dose. The volume of distribution of Corifollitropin alfa is Distribution, metabolism and elimination of corifollitropin alfa are very similar to other gonadotropins, such as FSH, hCG and LH. After absorption into the blood, corifollitropin alfa is distributed mainly to the ovaries and the kidneys. The steady-state volume of distribution is 9. 2 L. Exposure to corifollitropin alfa increases in a linear fashion with the dose within a range of 60 micrograms - 240 micrograms. No volume of distribution information is available for Pyrantel. No protein binding information is available for Corifollitropin alfa. No protein binding information is available for Pyrantel. Corifollitropin alfa metabolism: The metabolic fate of corifollitropin alfa highly resembles that of endogenous glycoprotein hormones, which predominantly is comprised of kidney clearance and the urinary excretion of the intact protein in parallel to kidney catabolism. Pyrantel metabolism: Pyrantel is administered orally. The poor solubility of the pamoate salt offers the advantage of reduced absorption from the gastrointestinal tract and allows the drug to reach and act against parasites in the large intestine. Metabolism of pyrantel is rapid. The absorbed drug is partly metabolized in the liver. Corifollitropin alfa is eliminated via Radioactivity labeling showed that the drug was mainly (86%) excreted in the urine. 90% of the radioactivity in serum was identified as [(125)I]corifollitropin alfa, but only 7-15% of the radioactivity in urine was identified as [(125)I]corifollitropin alfa and its dissociation products, the alpha- and beta-subunits (including its CTP part). Elimination of corifollitropin alfa mainly occurs via the kidneys. The elimination rate of this drug may be reduced in patients with renal insufficiency. Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa. Pyrantel is eliminated via Approximately 50% of an oral dose is excreted unchanged in feces; 7% excreted in urine as unchanged drug and metabolites. The half-life of Corifollitropin alfa is Corifollitropin alfa has a longer half-life compared with FSH and thus requires less frequent dosing. Corifollitropin alfa has an elimination half-life of 70 hours (59-82 hours). The half-life of Pyrantel is In pigs, following intravenous administration, pyrantel exhibited a half-life of 1. 75 +/- 0. 19 h. The clearance of Corifollitropin alfa is 0. 13 L/h (0. 10-0. 18 L/h1). No clearance information is available for Pyrantel. Corifollitropin alfa toxicity includes The most common side effects with Elonva (seen in between 1 and 10 patients in 100) include a headache, nausea, fatigue, pelvic pain and/or discomfort, breast tenderness and ovarian hyperstimulation syndrome (OHSS). This syndrome occurs when the ovaries have a heightened response to therapy, leading to abdominal swelling and pain, nausea and diarrhea. More than one injection of Elonva within one treatment cycle or an excessively high dose of Elonva and/or (rec)FSH can increase the risk of ovarian hyperstimulation syndrome, which may cause swollen or painful ovaries, abdominal bloating, nausea, and a weight gain of up to 3kg. In severe cases, ovarian hyperstimulation syndrome may cause rapid weight gain ranging from 15 to 20 kilograms in 5-10 days. Severe abdominal pain, severe, persistent nausea, and vomiting, decreased urination, and abdominal bloating, as well as other generalized symptoms, may occur. About 1 - 2 % of women undergoing ovarian stimulation develop a severe form of ovarian hyperstimulation syndrome (OHSS). Severe OHSS can be life-threatening. Complications may include: ascites, pulmonary edema, electrolyte disturbances (sodium, potassium, others), thrombosis in large vessels, usually in the lower extremities, renal failure, ovarian torsion, rupture of ovarian cysts. Some of these conditions can lead to hemorrhage, respiratory failure, spontaneous miscarriage or pregnancy termination due to complications, resulting in death. Pyrantel toxicity includes Mild adverse effects include nausea, vomiting, diarrhea, headache, and dizziness. LD50 in rats is 535 mg/kg. Reported effects in humans in case of overdose include gastrointestinal disturbance, central nervous system effects, and superficial skin reactions. In one study, serum aspartate aminotransferase (AST) and serum alanine-aminotransferase (ALT) values were increased in approximately 2% of patients. Pyrantel should be used with caution in patients with severe malnutrition or anemia. Supportive therapy is recommended for anemic, dehydrated, or malnourished patients before administration of the drug. Pyrantel pamoate has been placed in pregnancy category C. This refers to the fact that animal studies have revealed adverse effects on the fetus (teratogenic/embryocidal, or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Data on the use of pyrantel pamoate in pregnant women are quite limited. In mass treatment programs for which the World Health Organization (WHO) has observed that the benefits of treatment outweigh the risks, WHO allows the use of pyrantel pamoate in the 2nd and 3rd trimesters of pregnancy, due to the fact that the effects of pyrantel on birth outcome are uncertain. The risk of treatment in pregnant women already known to have an infection needs to be balanced with the risk of disease progression if treatment were to be omitted. Individuals with liver disease are more susceptible to the toxicity in cases of pyrantel overexposure,. There are no data regarding the presence of pyrantel in breast milk. Pyrantel is poorly absorbed from the GI tract; therefore, excretion into breast milk may be minimal. Some experts recommend that a single dose of pyrantel therapy may be given to breastfeeding women. Brand names of Corifollitropin alfa include Elonva. Brand names of Pyrantel include Pronto Plus Pinworm, Pyral. No synonyms are available for Corifollitropin alfa. No synonyms are available for Pyrantel. Corifollitropin alfa summary: It is Corifollitropin alfa is a FSH analogue indicated for Controlled Ovarian Stimulation (COS) in combination with a GnRH antagonist for the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) program. Pyrantel summary: It is Pyrantel is an anthelmintic used to treat helminth 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.

Corifollitropin alfa

Drug A is Amivantamab. Drug B is Estradiol acetate. The severity of the interaction is minor. Estradiol acetate may increase the thrombogenic activities of Amivantamab. 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. Amivantamab is indicated for Amivantamab is indicated in the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy. Estradiol acetate is indicated for Femring is indicated for the treatment of vasomotor and urogenital symptoms associated with menopause. Use of Femring (estradiol acetate) has been shown to improve symptoms caused by atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria). Amivantamab pharmacodynamics: Amivantamab is an EGF and MET receptor targeted antibody indicated in the treatment of non-small cell lung cancer with an EGFR 20 exon insertion mutation. It has a long duration of action, as activity can be detected up to 8 weeks after treatment. Patients should be counselled regarding the risk of infusion-related reactions, interstitial lung disease and pneumonitis, skin reactions, ocular toxicity, and paronychia. Patients should not take amivantamab if they are pregnant or breastfeeding. Estradiol acetate 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 Amivantamab is that it Mesenchymal-epithelial transition factor (MET) is a receptor with tyrosine kinase activity expressed on epithelial cells that, upon signalling, dimerizes and activates downstream pathways that signal cell division. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase activity that can further activate downstream pathways that signal cell division, survival, and angiogenesis. Patients with NSCLC with exon 20 insertion mutations in EGFR do not respond to tyrosine kinase inhibitors, and are generally treated with platinum-based therapy. Exon 20 insertion mutations in EGFR also lead to conformational changes that activate EGFR. Amivantamab targets both EGFR and MET, preventing ligands from binding to the receptors, blocking signalling, marking the cancerous cells for antibody-dependant cellular cytotoxicity by natural killer cells, and allowing macrophages to perform trogocytosis. Amivantamab's binding to the EGFR H epitope shares some of the same amino acids that cetuximab binds to. Amivantamab's binding to the alpha chain of MET stabilizes the Sema domain loop 1 to 2 in a position 6 Angstroms away from the position it would be in under normal binding, preventing its interaction with the hepatocyte growth factor's (HGF) beta chain. Another smaller conformational change in the MET Sema domain loop 1 to 3 also contributes to preventing the interaction of the MET Sema domain with HGF's beta chain. HGF is no longer able to bind to MET, preventing downstream signalling. Amivantamab's Fc portion contains 90% less fucose than normal antibodies, allowing for increased binding to the FcγRIIIa region. Binding of the Fc portion of Amivantamab signals the complement system and innate immune system to target the bound cells for complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis. Binding of amivantamab to the Fc receptor also leads to and increase in levels of IFNγ. Amivantamab also significantly downregulates the expression of EGFR and MET on NSCLC cell surfaces, further reducing downstream signalling. EGFR and MET on the cell surface are internalized, and possibly degrading by fusing endosomes with lysosomes. Alternatively, EGFR and MET are the subjects of monocyte-dependent trogocytosis. Trogocytosis allows monocytes to internalize and break down EGFR and MET from the NSCLC cells without cytotoxicity, downmodulating EGFR and MET receptors. The mechanism of action of Estradiol acetate 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. No absorption information is available for Amivantamab. Estradiol acetate absorption: Drug delivery from Femring is rapid for the first hour and then declines to a relatively constant rate for the remainder of the 3-month dosing interval. Estradiol acetate is rapidly hydrolyzed to estradiol which is absorbed through the vaginal mucosa as evidenced by the mean time to maximum concentration (tmax) for estradiol of about 1 hour (range 0. 25 to 1. 5 hrs). Following the maximum concentration (Cmax=1129pg/mL), serum estradiol decreases rapidly such that by 24 to 48 hours postdose, serum estradiol concentrations are relatively constant through the end of the 3-month dosing interval. The volume of distribution of Amivantamab is The mean volume of distribution of amivantamab-vmjw is 5. 13 ±1. 78 L. The volume of distribution of Estradiol acetate 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. No protein binding information is available for Amivantamab. Estradiol acetate is Estrogens circulate in the blood largely (>95%) bound to sex hormone binding globulin (SHBG) and to albumin. bound to plasma proteins. Amivantamab metabolism: Antibodies are expected to be metabolized to oligopeptides and amino acids. Estradiol acetate metabolism: Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. 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. Amivantamab is eliminated via No route of elimination available. Estradiol acetate is eliminated via Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life of Amivantamab is The terminal half life of amivantamab-vmjw is 11. 3 ± 4. 53 days. The half-life of Estradiol acetate is No half-life available. The clearance of Amivantamab is The mean clearance of amivantamab-vmjw is 360 ± 144 mL/day. No clearance information is available for Estradiol acetate. Amivantamab toxicity includes Data regarding overdoses of amivantamab are not readily available. Patients experiencing an overdose should be treated with symptomatic and supportive measures. Estradiol acetate toxicity includes Can cause nausea and vomiting, and withdrawal bleeding may occur in females. Brand names of Amivantamab include Rybrevant. Brand names of Estradiol acetate include Femring. No synonyms are available for Amivantamab. No synonyms are available for Estradiol acetate. Estradiol acetate Amivantamab summary: It is Amivantamab is an EGF and MET receptor targeted antibody indicated in the treatment of non-small cell lung cancer with an EGFR 20 exon insertion mutation. Estradiol acetate summary: It is Estradiol acetate is an estrogen used to treat vasomotor symptoms and moderate to severe vulvar and vaginal atrophy from menopause. 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.

Amivantamab

Drug A is Corticotropin. Drug B is Ublituximab. The severity of the interaction is moderate. The risk or severity of infection can be increased when Ublituximab is combined with Corticotropin. Prescribing information for Briumvi (ublituximab-xiiy) states that its co-administration with immunosuppressants (e. g. immunosuppressive doses of corticosteroids) may increase the risk of infection. Ublituximab, a B-cell depleting agent, is itself an immunosuppressive medication - the co-administration of ublituximab with agents exerting a similar effect may therefore result in additive immunosuppression and a subsequent increase in the risk of developing an infection. 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. Ublituximab is indicated for Ublituximab is indicated in adult patients for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease by the FDA. It is also indicated by the EMA to treat relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features. 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. Ublituximab pharmacodynamics: Treatment with ublituximab reduces CD19+ B-cell counts - used as a surrogate marker for CD20+ B-cells due to ublituximab's interference with the CD20 assay - within 24 hours of the initial infusion. The median time for B-cell counts to return to either baseline or the lower limit of normal (LLN) was 70. 3 weeks following the final infusion, and within 1. 5 years of the final infusion approximately 58% of patients had returned to baseline or LLN. 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 Ublituximab is that it B-cell dysregulation underlies the pathogenesis of various cancers and autoimmune conditions such as multiple sclerosis, neuromyelitis optica spectrum disease, and myelin oligodendrocyte glycoprotein IgG-associated disease. CD20 is an antigen expressed on pre-B cells, immature/mature B-cells, memory B-cells, and a subpopulation of CD3-positive T cells. Anti-CD20 antibodies can therefore induce B-cell depletion through direct cell death, induction of complement pathways, and Fc-gamma receptor (FcγR)-mediated phagocytosis (antibody-dependent cellular cytotoxicity, ADCC). Although several anti-CD20 antibodies have been developed, therapy has been hampered by low CD20 expression by malignant cells in diseases such as B-cell chronic lymphocytic leukemia and suboptimal antibody-dependent cytotoxicity. Ublituximab binds to an epitope on CD20 distinct from that bound by other approved antibodies such as rituximab, ofatumumab, obinutuzumab, and ocrelizumab, with a similar binding constant to rituximab. Uniquely, ublituximab is produced in the rat YB2/0 cell line such that it has a low fucose content (24% compared to 93% for rituximab ), improving its interaction with FcγR, especially FcγRIIIA (CD16) expressed by natural killer cells and macrophages. This difference grants ublituximab enhanced ADCC, including for low CD20-expressing malignant cells. The precise mechanism of action of ublituximab in the treatment of multiple sclerosis is unclear, but is presumed to involve CD20 binding and subsequent cell lysis as described above. Corticotropin absorption: Corticotropin is rapidly absorbed following intramuscular administration; the repository dosage form is slowly absorbed over approximately 8 to 16 hours. Ublituximab absorption: Following the administration of the approved recommended dosage of ublituximab, the geometric mean steady-state AUC was 3000 mcg/mL per day and the mean Cmax was 139 mcg/mL. In patients with relapsing multiple sclerosis, ublituximab exposure increases proportionally over a dose range of 150mg to 600mg. No volume of distribution information is available for Corticotropin. The volume of distribution of Ublituximab is The estimated central volume of distribution of ublituximab-xiiy was 3. 18 L. No protein binding information is available for Corticotropin. No protein binding information is available for Ublituximab. No metabolism information is available for Corticotropin. Ublituximab metabolism: As with other therapeutic proteins, the metabolism of ublituximab likely occurs via degradation to smaller peptides and amino acids by non-specific proteolytic enzymes. Corticotropin is eliminated via No route of elimination available. Ublituximab is eliminated via No route of elimination available. The half-life of Corticotropin is About 15 minutes following intravenous administration. The half-life of Ublituximab is The estimated mean terminal half-life of ublituximab-xiiy was 22 days. No clearance information is available for Corticotropin. No clearance information is available for Ublituximab. No toxicity information is available for Corticotropin. No toxicity information is available for Ublituximab. Brand names of Corticotropin include Acthar, Cortrophin. Brand names of Ublituximab include Briumvi. No synonyms are available for Corticotropin. No synonyms are available for Ublituximab. Corticotropin summary: It is Corticotropin is a diagnostic agent used in the screening of patients presumed to have adrenocortical insufficiency. Ublituximab summary: It is Ublituximab is a low-fucose CD20-targeted monoclonal antibody used in the treatment of relapsing forms of multiple sclerosis. Answer: Prescribing information for Briumvi (ublituximab-xiiy) states that its co-administration with immunosuppressants (e. g. immunosuppressive doses of corticosteroids) may increase the risk of infection. Ublituximab, a B-cell depleting agent, is itself an immunosuppressive medication - the co-administration of ublituximab with agents exerting a similar effect may therefore result in additive immunosuppression and a subsequent increase in the risk of developing an infection.

Corticotropin

Drug A is Basiliximab. Drug B is Natalizumab. The severity of the interaction is major. The risk or severity of immunosuppression can be increased when Basiliximab is combined with Natalizumab. Natalizumab is associated with a risk for immunosuppression, including progressive multifocal leukoencephalopathy (PML), and infections. 1,2,3 Because of the potential for increased risk of PML and other infections, natalizumab should not be concurrently used with other immunosuppressive agents, such as the subject drug. Basiliximab is indicated for prophylactic treatment of kidney transplant rejection. Natalizumab is indicated for Natalizumab is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults. It is also indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease with evidence of inflammation who have had an inadequate response to or are unable to tolerate, conventional therapies and inhibitors of TNF-α. It is not to be used in combination with immunosuppressants or inhibitors of TNF-α. Basiliximab pharmacodynamics: Basiliximab functions as an IL-2 receptor antagonist. Specifically it inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection. Natalizumab pharmacodynamics: Natalizumab is a disease-modifying drug that works to alleviate the symptoms of multiple sclerosis and Crohn’s disease by attenuating inflammation. A reduction in lesions was observed in patients with multiple sclerosis who received natalizumab. Natalizumab increases the number of circulating leukocytes, including lymphocytes, monocytes, basophils, and eosinophils; this effect is attributed to natalizumab inhibiting their transmigration out of the vascular space. Natalizumab does not affect the absolute count of circulating neutrophils. The mechanism of action of Basiliximab is that it Basiliximab binds with high-affinity to the alpha-subunit (CD25) of the high-affinity IL-2 receptor. This inhibits IL-2 binding, which inhibits T-cell activation and prevents the body from mounting an immune response against the foreign kidney. The mechanism of action of Natalizumab is that it Integrins are transmembrane receptors and adhesion molecules that facilitate the chemotaxis of leukocytes to inflammation sites. Made up of multiple subunits, α4 integrins form heterodimers with β-subunits to form functional molecules. During inflammation, endothelial cells lining blood vessels are activated by cytokines. There is increased expression of cell adhesion molecules on the vascular endothelium, such as vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), expressed on vascular endothelial cells of the gastrointestinal tract. These cell adhesion molecules act as ligands or counter-receptors for α4 integrin receptors expressed primarily on lymphocytes, monocytes, and eosinophils. The interaction between cell adhesion molecules and α4 integrin facilitates the transmigration of leukocytes across the endothelium into inflamed parenchymal tissue, activation and proliferation of lymphocytes, and enhanced activity of local cytokines and chemokines. α4 integrin can also interact with extracellular matrix molecules such as fibronectin and osteopontin to further propagate inflammation. Natalizumab binds to the α4 subunit of α4β1 and α4β7 integrin receptors to block the α4-mediated adhesion of leukocytes to their counter-receptors. In vitro, natalizumab also blocks α4-mediated cell binding to osteopontin and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). In vivo, natalizumab may further inhibit the interaction of α4-expressing leukocytes with their ligand(s) in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells. The specific mechanism(s) by which natalizumab exerts its effects in multiple sclerosis and Crohn’s disease have not been fully defined. Lesions in multiple sclerosis (MS) are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves the interaction between adhesion molecules on inflammatory cells and their counter-receptors expressed on endothelial cells lining blood vessels. Natalizumab blocks the molecular interaction of α4β1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain; thereby, natalizumab reduces leukocyte migration into brain parenchyma and reduces plaque formation associated with MS. The interaction of the α4β7 integrin with the endothelial receptor MAdCAM1 has been implicated as an important contributor to chronic inflammation in Crohn’s disease (CD). MAdCAM-1 is mainly expressed on gut endothelial cells and is critical in homing T lymphocytes to gut lymph tissue found in Peyer’s patches. Increased MAdCAM-1 expression is often observed at active inflammation sites in patients with CD, suggesting that MAdCAM-1 may be involved in the recruitment of leukocytes to the mucosa. The clinical effect of natalizumab in CD may, therefore, be secondary to the blockade of the molecular interaction of the α4ß7 integrin receptor with MAdCAM-1 expressed on the venular endothelium at inflammatory foci. VCAM-1 expression has been found to be upregulated on colonic endothelial cells in a mouse model of inflammatory bowel disease and appears to play a role in leukocyte recruitment to sites of inflammation; however, the role of VCAM-1 in CD is unclear. No absorption information is available for Basiliximab. Natalizumab absorption: Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD maximum observed serum concentration was 110 ± 52 mcg/mL. Mean average steady-state trough concentrations ranged from 23 mcg/mL to 29 mcg/mL. The observed time to steady-state was approximately 24 weeks after every four weeks of dosing. In patients with Crohn's Disease, the mean ± SD maximum observed serum concentration was 101 ± 34 mcg/mL. The mean ± SD average steady-state trough concentration was 10 ± 9 mcg/mL. The estimated time to steady-state was approximately 16 to 24 weeks after every four weeks of dosing. The volume of distribution of Basiliximab is 7. 8 ± 5. 1 L [Pediatric]. 4. 8 ± 2. 1 L [Adult] The volume of distribution of Natalizumab is Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD volume of distribution was 5. 7 ± 1. 9 L. In patients with Crohn's Disease, it was 5. 2 ± 2. 8 L. No protein binding information is available for Basiliximab. Natalizumab is No information is available. bound to plasma proteins. Basiliximab metabolism: Most likely removed by opsonization via the reticuloendothelial system when bound to lymphocytes, or by human antimurine antibody production. Natalizumab metabolism: No information is available. Basiliximab is eliminated via No route of elimination available. Natalizumab is eliminated via No information is available. The half-life of Basiliximab is 7. 2 +/- 3. 2 days (adults). The half-life of Natalizumab is Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD half-life was 11 ± 4 days. In patients with Crohn's Disease, it was 10 ± 7 days. The clearance of Basiliximab is 41 +/- 19 mL/h [Adult patients undergoing first kidney transplantation]. 17 +/- 6 mL/h [pediatric patients undergoing renal transplantation] 31 +/- 19 mL/h [adolescent patients undergoing renal transplantation] The clearance of Natalizumab is Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD clearance was 16 ± 5 mL/hour. In patients with Crohn's Disease, it was 22 ± 22 mL/hour. Natalizumab clearance increased with body weight in a less-than-proportional manner. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold. No toxicity information is available for Basiliximab. Natalizumab toxicity includes There is limited information regarding the acute toxicity (LD 50 ) and overdosage of natalizumab. The safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of natalizumab that can be safely administered has not been determined. Brand names of Basiliximab include Simulect. Brand names of Natalizumab include Tysabri. No synonyms are available for Basiliximab. No synonyms are available for Natalizumab. Basiliximab summary: It is Basiliximab is a monoclonal anti-C25 antibody (interleukin-2 receptor alpha subunit) used as immunosuppressive therapy in kidney transplant patients. Natalizumab summary: It is Natalizumab is a monoclonal anti-integrin antibody used to treat Crohn's disease or multiple sclerosis. Answer: Natalizumab is associated with a risk for immunosuppression, including progressive multifocal leukoencephalopathy (PML), and infections. 1,2,3 Because of the potential for increased risk of PML and other infections, natalizumab should not be concurrently used with other immunosuppressive agents, such as the subject drug.

Basiliximab

Drug A is Obinutuzumab. Drug B is Bamlanivimab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Obinutuzumab is combined with Bamlanivimab. 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. Bamlanivimab is indicated for Bamlanivimab is not currently approved for any indication by the FDA. Bamlanivimab is authorized under an Emergency Use Authorization (EUA) for the treatment of mild to moderate COVID-19 in patients aged 12 years and older weighing at least 40 kg who are at high risk for progressing to severe COVID-19 and/or hospitalization due to COVID-19. Patients should have confirmed COVID-19, with identification of SARS-CoV-2 viral load by an approved test. Under this EUA, bamlanivimab is not authorized in patients who are hospitalized due to COVID-19, who require oxygen due to COVID-19, or in patients on oxygen therapy for non-COVID-19-related comorbidity who require an increased oxygen flow rate due to COVID-19. Bamlanivimab in combination with etesevimab is used to treat mild to moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients, including neonates, with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. This combination regimen is also used for post-exposure prophylaxis of COVID-19 in unvaccinated or immunocompromised adults and pediatric individuals, including neonates, who are at high risk of progression to severe COVID-19, including hospitalization or death. Obinutuzumab pharmacodynamics: Obinutuzumab is more potent than rituximab in depleting B-cells, antitumor activity, and tumor regression. Bamlanivimab pharmacodynamics: Bamlanivimab is a recombinant human IgG1κ monoclonal antibody directed against the spike (S) surface protein of SARS-CoV-2. Patients in a phase 2 trial were administered up to 7000 mg (ten times the authorized dose) with no increase in treatment-related adverse effects and a flat exposure-response relationship over ranges of 700-7000 mg. Despite generally mild adverse effects noted in the phase 2 trial, there is a risk of serious infusion-related hypersensitivity reactions with bamlanivimab, including anaphylaxis, which may necessitate slowing the infusion rate or discontinuing treatment entirely. 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 Bamlanivimab is that it Bamlanivimab is a neutralizing recombinant human IgG1κ monoclonal antibody directed against the spike (S) surface protein of SARS-CoV-2 derived from screening antigen-specific B-cells from a convalescent COVID-19 patient. X-ray crystallography and cryo-EM structural determination suggest that bamlanivimab binds the receptor-binding domain (RBD) of the S protein at a position overlapping the ACE2 binding site and which is accessible in both the up and down conformations of the RBD. Specifically, bamlanivimab binds to the S protein with a K D of 0. 071 nM and blocks S protein-ACE2 interactions with an IC 50 value of 0. 025 μg/mL. Obinutuzumab absorption: Obinutuzumab is administered intravenously, so its absorption is 100%. No absorption information is available for Bamlanivimab. The volume of distribution of Obinutuzumab is Obinutuzumab has a volume of distribution of about 3. 8 L. No volume of distribution information is available for Bamlanivimab. Obinutuzumab is Obinutuzumab does not bind to plasma proteins. bound to plasma proteins. No protein binding information is available for Bamlanivimab. Obinutuzumab metabolism: Obinutuzumab is not metabolized by the liver. Bamlanivimab metabolism: As a monoclonal antibody, it is expected that bamlanivimab will be degraded by proteases in various locations throughout the body. Bamlanivimab is not metabolized by cytochrome P450 enzymes, making drug interactions unlikely. Obinutuzumab is eliminated via The route of elimination of obinutuzumab was not indicated (FDA label). Bamlanivimab is eliminated via No route of elimination available. The half-life of Obinutuzumab is The half life of obinutuzumab is 28. 4 days. The half-life of Bamlanivimab is No half-life available. The clearance of Obinutuzumab is The clearance of obinutuzumab is 0. 09L/day. No clearance information is available for Bamlanivimab. 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. Bamlanivimab toxicity includes Bamlanivimab has been administered at doses of 7000 mg (ten times the authorized dose) during phase 2 clinical trials without any observed dose-limiting toxicity. In the event of an overdose, the recommended treatment is symptomatic and supportive measures; there is no antidote for bamlanivimab overdose. Brand names of Obinutuzumab include Gazyva. Brand names of Bamlanivimab include No brand names available. No synonyms are available for Obinutuzumab. No synonyms are available for Bamlanivimab. Obinutuzumab summary: It is Obinutuzumab is an antineoplastic CD20 antibody used to treat untreated chronic lymphocytic leukemia in combination with chlorambucil. Bamlanivimab summary: It is Bamlanivimab is a neutralizing human IgG1κ monoclonal antibody against the SARS-CoV-2 spike (S) protein for use in patients aged 12 and over at high risk of developing severe COVID-19. 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 Bupropion. Drug B is Diphenoxylate. The severity of the interaction is moderate. The risk or severity of CNS depression can be increased when Diphenoxylate is combined with Bupropion. 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. Bupropion is indicated for Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e. g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. Diphenoxylate is indicated for as adjunctive therapy in the management of diarrhea. Bupropion pharmacodynamics: Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1. 3 mmHg. Diphenoxylate pharmacodynamics: Diphenoxylate, an antidiarrheal, is effective as adjunctive therapy in the management of diarrhea. Diphenoxylate is rapidly and extensively metabolized in man by ester hydrolysis to diphenoxylic acid (difenoxine), which is biologically active and the major metabolite in the blood. The mechanism of action of Bupropion is that it Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. The mechanism of action of Diphenoxylate is that it Diphenoxylate is an opiate receptor agonists that stimulate mu receptors in GI to decrease the peristalsis and constrict the sphincters. Diphenoxylate has a direct effect on circular smooth muscle of the bowel, that conceivably results in segmentation and prolongation of gastrointestinal transit time. The clinical antidiarrheal action of diphenoxylate may thus be a consequence of enhanced segmentation that allows increased contact of the intraluminal contents with the intestinal mucosa. Bupropion absorption: Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i. e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1. 5 and 7 times that of bupropion, respectively. Diphenoxylate absorption: 90%. No volume of distribution information is available for Bupropion. No volume of distribution information is available for Diphenoxylate. Bupropion is In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. bound to plasma proteins. Diphenoxylate is 74-95% bound to plasma proteins. Bupropion metabolism: Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. Diphenoxylate metabolism: Hepatic. Bupropion is eliminated via Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0. 5%, a finding consistent with the extensive metabolism of bupropion. Diphenoxylate is eliminated via No route of elimination available. The half-life of Bupropion is 24 hours. The half-life of Diphenoxylate is 12-14 hours. No clearance information is available for Bupropion. No clearance information is available for Diphenoxylate. Bupropion toxicity includes Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. Diphenoxylate toxicity includes Coma, dry skin and mucous membranes, enlarged pupils of the eyes, extremely high body temperature, flushing, involuntary eyeball movement, lower than normal muscle tone, pinpoint pupils, rapid heartbeat, restlessness, sluggishness, suppressed breathing. Brand names of Bupropion include Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban. Brand names of Diphenoxylate include Lomotil. No synonyms are available for Bupropion. No synonyms are available for Diphenoxylate. Difenoxilato Diphenoxylate Diphenoxylatum Bupropion summary: It is Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. Diphenoxylate summary: It is Diphenoxylate is an antidiarrheal medication used with atropine to manage diarrhea. 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.

Bupropion

Drug A is Blinatumomab. Drug B is Edoxaban. The severity of the interaction is minor. The risk or severity of bleeding can be increased when Edoxaban is combined with Blinatumomab. 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. Blinatumomab is indicated for Blinatumomab is indicated for the treatment of adults and children with relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). It is also indicated in adults and children for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0. 1%. Edoxaban is indicated for Edoxaban is indicated for reducing the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). However, it should not be used in patients with creatinine clearance (CrCL) > 95 mL/min because of increased risk of ischemic stroke compared to warfarin at the highest dose studied (60 mg). It is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5-10 days of initial therapy with a parenteral anticoagulant. Blinatumomab pharmacodynamics: Blinatumomab promoted peripheral T-cell redistribution at the start of infusion or dose escalation. In most patients, T-cell counts were lower in the first 1-2 days of treatment and returned to baseline levels within 7-14 days. An increase in T-cell levels, also known as T-cell expansion, was observed in a few patients. In the first treatment cycle, blinatumomab doses higher than ≥ 5 mcg/m2/day or ≥ 9 mcg/day decreased peripheral B-cell counts to 10 cells/microliter or less. During the blinatumomab-free period between treatment cycles (2 weeks), peripheral B-cell counts did not recover. The use of blinatumomab may lead to an elevation of IL-6, IL-10, and IFN-γ; however, cytokine levels return to baseline within 24 to 48 hours. Blinatumomab may lead to the development of cytokine release syndrome, neurological toxicities, infections, tumor lysis syndrome, neutropenia and febrile neutropenia, pancreatitis, leukoencephalopathy and transient elevations in liver enzymes. The use of blinatumomab can also affect a patient’s ability to drive and use machines. Edoxaban pharmacodynamics: Administration of edoxaban results in prolongation of clotting time tests such as aPTT (activated partial thromboplastin time), PT (prothrombin time), and INR (international normalized ratio). The mechanism of action of Blinatumomab is that it Blinatumomab is a bispecific T-cell engager (BiTE) that targets CD19, an antigen expressed on the surface of B-cells, and CD3, an antigen expressed on the surface of T-cells. B-cell malignancies, such as acute lymphoblastic leukemia (ALL), express high levels of CD19, making it a therapeutic target for the treatment of these conditions. Blinatumomab recruits and activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on both benign and malignant B cells. By bringing T-cells and tumor cells together, blinatumomab induces an immune response that leads to T-cell activation and proliferation. It promotes the release of cytokines such as TNF-α, IFN-γ, IL-6, and IL-10 by T-cells, the induction of activation markers, such as CD69 and CD25, and the expression of adhesion molecules on the T-cell surface. Altogether, blinatumomab promotes the lysis of CD19+ tumor cells. The mechanism of action of Edoxaban is that it Edoxaban is a selective inhibitor of factor Xa, a serine endopeptidase of the clotting cascade required for cleavage of prothrombin into thrombin. Blinatumomab absorption: In adult patients, the pharmacokinetic profile of blinatumomab appears to be linear between 5 to 90 mcg/m /day (equivalent to 9 to 162 mcg/day). The steady-state serum concentration (C ss ) of blinatumomab was achieved within a day of continuous intravenous infusion, and in the range tested, the mean C ss was approximately dose-proportional. At the clinical doses for the treatment of relapsed or refractory acute lymphoblastic leukemia (9 mcg/day and 28 mcg/day), the C ss was 228 (356) pg/mL and 616 (537) pg/mL, respectively. Edoxaban absorption: Following oral administration, peak plasma edoxaban concentrations are observed within 1-2 hours. Absolute bioavailability is 62%. The volume of distribution of Blinatumomab is Blinatumomab has a volume of distribution based on terminal phase of 4. 35 L. The volume of distribution of Edoxaban is The steady state volume of distribution is 107 L. No protein binding information is available for Blinatumomab. Edoxaban is In vitro plasma protein binding is ~55%. bound to plasma proteins. Blinatumomab metabolism: The metabolic pathway of blinatumomab has not been characterized. As a monoclonal antibody, blinatumomab is expected to be metabolized into small peptides and amino acids via catabolic pathways. Edoxaban metabolism: Edoxaban is not extensively metabolized by CYP3A4 resulting in minimal drug-drug interactions. However, it does interact with drugs that inhibit p-gp (p-glycoprotein), which is used to transport edoxaban across the intestinal wall. Unchanged edoxaban is the predominant form in plasma. There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4. The predominant metabolite M-4, formed by hydrolysis, is human-specific and active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban. Blinatumomab is eliminated via At clinical doses, negligible amounts of blinatumomab were excreted in the urine. Edoxaban is eliminated via Edoxaban is eliminated primarily as unchanged drug in urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion account for the remaining clearance. The half-life of Blinatumomab is Blinatumomab has a half-life of 2. 10 hours. In pediatric patients, the half-life was 2. 19 hours in the first cycle of blinatumomab at the recommended dose. The half-life of Edoxaban is The terminal elimination half-life of edoxaban following oral administration is 10 to 14 hours. The clearance of Blinatumomab is Blinatumomab has an estimated systemic clearance of 3. 11 L/hour in patients receiving blinatumomab with continuous intravenous infusion. There is a 2-fold difference in clearance values between patients with normal renal function and those with moderate renal impairment. Pediatric patients had an estimated clearance of 1. 88 L/hour/m in the first cycle of blinatumomab at the recommended dose. The clearance of Edoxaban is 22 L/hr. Blinatumomab toxicity includes Blinatumomab overdose cases have been reported, including a patient that received 133-fold the recommended therapeutic dose over a short period of time. In a study that included pediatric and adolescent patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), a patient receiving 30 mcg/m2/day of blinatumomab (higher than the maximum tolerated dose) experienced a fatal cardiac failure event in the setting of life-threatening cytokine release syndrome (CRS). The adverse reactions observed during blinatumomab overdoses included fever, tremors, and headache, consistent with those observed at the recommended dose. If a patient is experiencing an overdose, the blinatumomab product label recommends to interrupt the infusion, monitor the patient for signs of adverse reactions, and provide supportive care. Re-initiating blinatumomab at the recommended dose should be considered after all adverse reactions have been resolved and no earlier than 12 hours after the infusion is interrupted. The carcinogenic, genotoxic, and fertility effects of blinatumomab have not been evaluated. Edoxaban toxicity includes Premature discontinuation of any oral anticoagulant, including edoxaban, in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If edoxaban is discontinued for reasons other than pathological bleeding or completion of a course of therapy, consider the use of another anticoagulant. Edoxaban increases the risk of potentially fatal major bleeding such as intracranial hemorrhage and gastrointestinal bleeding. Patients should be educated on how to watch for signs of major and minor bleeding and when to seek medical help. Co-administration of other anti-coagulants, anti-platelets, or thrombolytics may increase the risk of bleeding and should therefore be avoided. Brand names of Blinatumomab include Blincyto. Brand names of Edoxaban include Lixiana, Savaysa. No synonyms are available for Blinatumomab. No synonyms are available for Edoxaban. Blinatumomab summary: It is Blinatumomab is an antineoplastic antibody used to treat CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in relapsed and refractory patients, as well as those in first or second complete remission with minimal residual disease (MRD). Edoxaban summary: It is Edoxaban is a novel oral anticoagulant used for reducing the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). 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.

Blinatumomab

Drug A is Belantamab mafodotin. Drug B is Obinutuzumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Obinutuzumab is combined with Belantamab mafodotin. 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. 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. Obinutuzumab is indicated for Obinutuzumab is used as a combination treatment with chlorambucil to treat patients with untreated chronic lymphocytic leukemia. 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. Obinutuzumab pharmacodynamics: Obinutuzumab is more potent than rituximab in depleting B-cells, antitumor activity, and tumor regression. 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 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. 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. Obinutuzumab absorption: Obinutuzumab is administered intravenously, so its absorption is 100%. 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 Obinutuzumab is Obinutuzumab has a volume of distribution of about 3. 8 L. Belantamab mafodotin is Monoclonal antibodies are generally not protein bound. bound to plasma proteins. Obinutuzumab is Obinutuzumab does not bind to plasma proteins. 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. Obinutuzumab metabolism: Obinutuzumab is not metabolized by the liver. 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. Obinutuzumab is eliminated via The route of elimination of obinutuzumab was not indicated (FDA label). 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 Obinutuzumab is The half life of obinutuzumab is 28. 4 days. 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. The clearance of Obinutuzumab is The clearance of obinutuzumab is 0. 09L/day. Belantamab mafodotin toxicity includes Data regarding overdose is not readily available. However, keratopathy was seen in 71% of patients. 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. Brand names of Belantamab mafodotin include BLENREP. Brand names of Obinutuzumab include Gazyva. No synonyms are available for Belantamab mafodotin. No synonyms are available for Obinutuzumab. 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. Obinutuzumab summary: It is Obinutuzumab is an antineoplastic CD20 antibody used to treat untreated chronic lymphocytic leukemia in combination with chlorambucil. 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.

Belantamab mafodotin

Drug A is Omalizumab. Drug B is Inebilizumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Omalizumab is combined with Inebilizumab. 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 Inebilizumab is indicated for Inebilizumab is indicated for the treatment of aquaporin-4 (AQP4) immunoglobulin-positive (AQP4-IgG) neuromyelitis optica spectrum disorder (NMOSD) in adult patients. 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. Inebilizumab pharmacodynamics: Inebilizumab is a CD19-directed monoclonal antibody that results in immunosuppression through B-cell depletion with sufficient efficacy to allow a six-month dosing schedule. Due to this mechanism of action, patients undergoing inebilizumab treatment may be at higher risk of infections and should be monitored for active infections and immunoglobulin levels while undergoing treatment; vaccination is not recommended during inebilizumab treatment. Also, there is a risk of severe infusion reactions. Animal data suggests the possibility of fetal harm with inebilizumab and therefore, effective contraception during and for six months following inebilizumab treatment is recommended. 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 Inebilizumab is that it Neuromyelitis optica spectrum disorder (NMOSD), formerly referred to as Devic's disease, is an antibody-mediated autoimmune condition resulting in astroglial cell death, demyelination, and central nervous system (CNS) inflammation. The presence of anti-aquaporin 4 immunoglobulin (AQP4-IgG) is the most frequent biomarker, although AQP4-IgG negative, anti-myelin oligodendrocyte glycoprotein (anti-MOG) positive, variants with similar presentation also exist. The theoretical origin of symptoms is through AQP4-IgG-mediated astrocyte cytotoxicity and subsequent infiltration of neutrophils, eosinophils, and macrophages, leading to inflammatory-mediated oligodendrocyte damage and myelin sheath loss. In general, this manifests as optic neuritis and transverse myelitis with occasional involvement of the diencephalic, brainstem, and cerebral hemisphere. CD19 is a B-cell surface antigen expressed on most B-cells, including the expanded population of CD27 CD38 CD180 CD19 plasmablasts that are the origin of astrocytic AQP4-IgG in most NMOSD patients. Inebilizumab binds to CD19 and, through one of several potential mechanisms, results in cell death. Destruction of the specific AQP4-IgG-producing plasmablasts results in lower amounts of AQP4-IgG in the CNS and therefore slows neuronal damage and improves patient outcomes. 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. Inebilizumab absorption: Inebilizumab is given intravenously and hence is immediately exposed to the systemic circulation. The mean reported Cmax following second dose 300 mg administration was 108 μg/mL, and the cumulative AUC following 26 weeks of treatment with two IV administrations was 2980 μg*d/mL. In a clinical trial investigating the use of inebilizumab in relapsing multiple sclerosis, the mean Cmax corresponding to 30, 100, and 600 mg of inebilizumab was 17. 9, 43. 1, and 248. 0 μg/mL and the AUC 0-∞ was 440, 1150, and 6950 μg*d/mL. In another trial for patients with systemic sclerosis, the mean Cmax varied between 2. 7 and 227. 0 μg/mL and the AUC 0-∞ varied between 16. 1 and 2890. 0 μg*d/mL for doses between 0. 1 and 10. 0 mg/kg. 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 Inebilizumab is Inebilizumab has an estimated central volume of distribution of 2. 95L and a peripheral volume of distribution of 2. 57L. The steady-state volume of distribution in patients administered with a range of doses between 0. 1 and 10. 0 mg/kg ranged from 53. 7 to 71. 7 mL/kg. Omalizumab is Monoclonal antibodies are usually not required to have protein binding studies. bound to plasma proteins. No protein binding information is available for Inebilizumab. 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. Inebilizumab metabolism: Inebilizumab is a monoclonal antibody and is hence likely degraded through proteolysis. 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. Inebilizumab is eliminated via No route of elimination available. 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 Inebilizumab is Inebilizumab exhibits biphasic pharmacokinetics with a mean terminal half-life of 18 days. The terminal half-life reported in phase I studies varied by dose but was typically close to 18 days, with a range of 6. 8 to 18. 7 days. 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). The clearance of Inebilizumab is Inebilizumab has an estimated systemic clearance of 0. 19 L/day. In phase I studies, the reported clearance varied between 139-180 mL/day in one study, and 3. 5-6. 2 mL/kg/day in another, depending on the dose. 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. Inebilizumab toxicity includes Toxicity information regarding inebilizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as severe infusion reactions, infections, and arthralgia. Symptomatic and supportive measures are recommended. Brand names of Omalizumab include Xolair. Brand names of Inebilizumab include Uplizna 3 Vial Kit. No synonyms are available for Omalizumab. No synonyms are available for Inebilizumab. Omalizumab summary: It is Omalizumab is a monoclonal anti-immunoglobulin E antibody used in the treatment of severe asthma and chronic idiopathic urticaria. Inebilizumab summary: It is Inebilizumab is a humanized anti-CD19 cytolytic monoclonal antibody for B-cell depletion in autoimmune conditions. Currently approved only for neuromyelitis optica spectrum disorder (NMOSD). 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 Bupropion. Drug B is Infliximab. The severity of the interaction is moderate. The metabolism of Bupropion can be increased when combined with Infliximab. 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 CYP2B6 substrates. Bupropion is indicated for Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e. g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. Infliximab is indicated for Indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult or pediatric (≥ 6 years of age) patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy Indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease. Indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult or pediatric (≥ 6 years of age) patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy. Indicated for, in combination with methotrexate, reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. Indicated for reducing signs and symptoms in patients with active ankylosing spondylitis. Indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis. Indicated for the treatment of adult patients with chronic severe (i. e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. Bupropion pharmacodynamics: Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1. 3 mmHg. Infliximab pharmacodynamics: Infliximab disrupts the activation of pro-inflammaory cascade signalling. Infliximab has shown to reduce infiltration of inflammatory cells into sites of inflammation. It also attenautes the expression of molecules mediating cellular adhesion {including E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)}, chemoattraction {[IL-8 and monocyte chemotactic protein (MCP-1)} and tissue degradation {matrix metalloproteinase (MMP) 1 and 3}. The mechanism of action of Bupropion is that it Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. The mechanism of action of Infliximab is that it Infliximab is a IgG1κ monoclonal antibody that binds to soluble and transmembrane forms of TNF-α with high affinity to disrupt the pro-inflammatory cascade signalling. Binding of the antibody to TNF-α prevents TNF-α from interacting with its receptors. Infliximab does not neutralize TNF-β (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNF-α. Blocked actions of TNF-α further leads to downregulation of local and systemic pro-inflammatory cytokines (i. e. IL-1, IL-6), reduction of lymphocyte and leukocyte migration to sites of inflammation, induction of apoptosis of TNF-producing cells (i. e. activated monocytes and T lymphocytes), increased levels of nuclear factor-κB inhibitor, and reduction of reduction of endothelial adhesion molecules and acute phase proteins. Its inhibitory actions on TNF-α was demonstrated in human fibroblasts, endothelial cells, neutrophils, B and Tlymphocytes and epithelial cells. Infliximab also atteunates the production of tissue degrading enzymes synthesized by synoviocytes and/or chondrocytes. According to a transgenic mice study that developed polyarthritis due to consitutive levels of human TNF-α, infliximab decreased synovitis and joint erosions in collagen-induced arthritis and allows eroded joints to heal. Bupropion absorption: Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i. e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1. 5 and 7 times that of bupropion, respectively. Infliximab absorption: Following a single intravenous infusion, infliximab absorption displays a linear relationship between the dose administered and the maximum serum concentration. In patients with Crohn's disease, the maximum plasma concentration (Cmax) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 75 µg/mL and 181 µg/mL, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in Cmax of 120 µg/mL and 189 µg/mL, respectively. In patients with rheumatoid arthritis, the Cmax of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 192±51 µg/mL, 427±106 µg/mL, and 907±183 µg/mL, respectively. No volume of distribution information is available for Bupropion. The volume of distribution of Infliximab is Based on a pharmacokinetic study of adult patients, the distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. In patients with Crohn's disease, the apparent volume of distribution at steady state (Vss) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 80 mL/kg and 65 mL/kg, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in Vss of 70 mL/kg and 81 mL/kg, respectively. In patients with rheumatoid arthritis, the Vss of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 4. 3±2. 5 L, 3. 2±0. 7 L, and 3. 1±0. 6 L, respectively. Bupropion is In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. bound to plasma proteins. No protein binding information is available for Infliximab. Bupropion metabolism: Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. No metabolism information is available for Infliximab. Bupropion is eliminated via Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0. 5%, a finding consistent with the extensive metabolism of bupropion. Infliximab is eliminated via Therapeutic monoclonal antibodies including infliximab are predicted to be nonspecifically metabolized to peptides and amino acids that can be re-used in the body for de novo synthesis of proteins or arc excreted by the kidney. The reticuloendothelial system (RES) are phagocytic cells of the immune system such as macrophages and monocytes that play a role in the elimination of endogenous IgG antibodies. Although administered infliximab accounts for a small fraction of total endogenous IgG and this route is not likely saturated by therapeutic mAbs, infliximab may be removed by opsonization via RES following binding of the Fc part of the antibody to Fcy-receptors expressed on the RES. The half-life of Bupropion is 24 hours. The half-life of Infliximab is The median terminal half-life of infliximab is 7. 7 to 9. 5 days. The data is based on a pharmacokinetic study in patients with Crohn's disease, plaque psoriasis and rheumatoid arthritis receiving a single dose of infliximab. No clearance information is available for Bupropion. The clearance of Infliximab is In patients with Crohn's disease, the total body clearance (CL) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 18. 4 mL/h and 14. 3 mL/h, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in CL of 15. 2 mL/h and 15. 2 mL/h, respectively. In patients with rheumatoid arthritis, the CL of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 11±7. 5 mL/h, 11. 4±5 mL/h, and 11±8. 9 mL/h, respectively. Development of antibodies to infliximab increased infliximab clearance. Bupropion toxicity includes Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. Infliximab toxicity includes In an acute toxicity animal study, the NOAEL of intravenous infliximab in rats was 50 mg/kg. In a repeated dose animal study, the NOAEL values of intravenous infliximab was 50 mg/kg in rats at 2 weeks following 3 doses and 40 mg/kg/day in mice at 6 months. The toxicological potential of infliximab in humans has not yet been fully established. According to an analogous antibody study, infliximab is not predicted to induce tumorigenic, clastogenic or mutagenic effects. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study. Brand names of Bupropion include Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban. Brand names of Infliximab include Avsola, Flixabi, Inflectra, Remicade, Renflexis, Zymfentra. No synonyms are available for Bupropion. No synonyms are available for Infliximab. Bupropion summary: It is Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. Infliximab summary: It is Infliximab 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. 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 CYP2B6 substrates.

Bupropion

Drug A is Adenosine. Drug B is Verapamil. The severity of the interaction is moderate. Adenosine may increase the arrhythmogenic activities of Verapamil. The subject and the affected drugs are antiarrhythmic drugs with some pro-arrhythmic potentials, such as arrhythmia, QT prolongation, conduction disturbances, and bradycardia. The co-administration of antiarrhythmic agents can result in additive effects and an increased risk of developing these adverse effects. Adenosine is indicated for Adenosine is indicated as an adjunct to thallium-201 in myocardial perfusion scintigraphy in patients unable to adequately exercise. It is also indicated to convert sinus rhythm of paroxysmal supraventricular tachycardia. Verapamil is indicated for Verapamil is indicated in the treatment of vasopastic (i. e. Prinzmetal's) angina, unstable angina, and chronic stable angina. It is also indicated to treat hypertension, for the prophylaxis of repetitive paroxysmal supraventricular tachycardia, and in combination with digoxin to control ventricular rate in patients with atrial fibrillation or atrial flutter. Given intravenously, it is indicated for the treatment of various supraventricular tachyarrhythmias, including rapid conversion to sinus rhythm in patients with supraventricular tachycardia and for temporary control of ventricular rate in patients with atrial fibrillation or atrial flutter. Verapamil is commonly used off-label for prophylaxis of cluster headaches. Adenosine pharmacodynamics: Adenosine is indicated as an adjunct to thallium-201 in myocardial perfusion scintigraphy and also indicated for conversion of sinus rhythm of paroxysmal supraventricular tachycardia. Adenosine has a short duration of action as the half life is <10 seconds, and a wide therapeutic window. Patients should be counselled regarding the risk of cardiovascular side effects, bronchoconstriction, seizures, and hypersensitivity. Verapamil pharmacodynamics: Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive activity. Immediate-release verapamil has a relatively short duration of action, requiring dosing 3 to 4 times daily, but extended-release formulations are available that allow for once-daily dosing. As verapamil is a negative inotropic medication (i. e. it decreases the strength of myocardial contraction), it should not be used in patients with severe left ventricular dysfunction or hypertrophic cardiomyopathy as the decrease in contractility caused by verapamil may increase the risk of exacerbating these pre-existing conditions. The mechanism of action of Adenosine is that it Agonism of adenosine receptors A1 and A2 reduces conduction time in the atrioventricular node of the heart. Conduction time is decreased by inducing potassium efflux and inhibiting calcium influx through channels in nerve cells, leading to hyperpolarization and increased threshold for calcium dependent action potentials. Decreased conduction time leads to an antiarrhythmic effect. Inhibition of calcium influx, reduces the activity of adenylate cyclase, relaxing vascular smooth muscle. Relaxed vascular smooth muscle leads to increased blood flow through normal coronary arteries but not stenotic arteries, allowing thallium-201 to be more readily uptaken in normal coronary arteries. The mechanism of action of Verapamil is that it Verapamil inhibits L-type calcium channels by binding to a specific area of their alpha-1 subunit, Cav1. 2, which is highly expressed on L-type calcium channels in vascular smooth muscle and myocardial tissue where these channels are responsible for the control of peripheral vascular resistance and heart contractility. Calcium influx through these channels allows for the propagation of action potentials necessary for the contraction of muscle tissue and the heart's electrical pacemaker activity. Verapamil binds to these channels in a voltage- and frequency-dependent manner, meaning affinity is increased 1) as vascular smooth muscle membrane potential is reduced, and 2) with excessive depolarizing stimulus. Verapamil's mechanism of action in the treatment of angina and hypertension is likely due to the mechanism described above. Inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation - this lowers systemic vascular resistance (i. e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina. Electrical activity through the AV node is responsible for determining heart rate, and this activity is dependent upon calcium influx through L-type calcium channels. By inhibiting these channels and decreasing the influx of calcium, verapamil prolongs the refractory period of the AV node and slows conduction, thereby slowing and controlling the heart rate in patients with arrhythmia. Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to result from an effect on other calcium channels (e. g. N-, P-, Q-, or T-type). Verapamil is known to interact with other targets, including other calcium channels, potassium channels, and adrenergic receptors. Adenosine absorption: Data regarding the absorption of adenosine are not readily available. Verapamil absorption: More than 90% of orally administered verapamil is absorbed - despite this, bioavailability ranges only from 20% to 30% due to rapid biotransformation following first-pass metabolism in the portal circulation. Absorption kinetic parameters are largely dependent on the specific formulation of verapamil involved. Immediate-release verapamil reaches peak plasma concentrations (i. e. Tmax ) between 1-2 hours following administration, whereas sustained-release formulations tend to have a Tmax between 6 - 11 hours. AUC and Cmax values are similarly dependent upon formulation. Chronic administration of immediate-release verapamil every 6 hours resulted in plasma concentrations between 125 and 400 ng/mL. Steady-state AUC₀–₂₄h and Cmax values for a sustained-release formulation were 1037 ng∙h/ml and 77. 8 ng/mL for the R-isomer and 195 ng∙h/ml and 16. 8 ng/mL for the S-isomer, respectively. Interestingly, the absorption kinetics of verapamil are highly stereospecific - following oral administration of immediate-release verapamil every 8 hours, the relative systemic availability of the S-enantiomer compared to the R-enantiomer was 13% after a single dose and 18% at steady-state. The volume of distribution of Adenosine is Data regarding the volume of distribution of adenosine are not readily available. The volume of distribution of Verapamil is Verapamil has a steady-state volume of distribution of approximately 300L for its R-enantiomer and 500L for its S-enantiomer. Adenosine is Adenosine is bound to albumin in plasma, however data regarding the extent of binding are not readily available. bound to plasma proteins. Verapamil is Verapamil is extensively protein-bound in plasma. R-verapamil is 94% bound to serum albumin while S-verapamil is 88% bound. Additionally, R-verapamil is 92% bound to alpha-1 acid glycoprotein and S-verapamil is 86% bound. bound to plasma proteins. Adenosine metabolism: Adenosine can be phosphorylated by adenosine kinase to form adenosine monophosphate. From there, it is phosphorylated again by adenylate kinase 1 to form adenosine diphosphate, and again by nucleoside diphosphate kinase A or B to form adenosine triphosphate. Alternatively, adenosine can be deaminated by adenosine deaminase to form inosine. Iosine is phosphorylated by purine nucleoside phosphorylase to form hypoxanthine. Hypoxanthine undergoes oxidation by xanthine dehydrogenase twice to form the metabolites xanthine, followed by uric acid. Verapamil metabolism: Verapamil is extensively metabolized by the liver, with up to 80% of an administered dose subject to elimination via pre-systemic metabolism - interestingly, this first-pass metabolism appears to clear the S-enantiomer of verapamil much faster than the R-enantiomer. The remaining parent drug undergoes O-demethylation, N-dealkylation, and N-demethylation to a number of different metabolites via the cytochrome P450 enzyme system. Norverapamil, one of the major circulating metabolites, is the result of verapamil's N-demethylation via CYP2C8, CYP3A4, and CYP3A5, and carries approximately 20% of the cardiovascular activity of its parent drug. The other major pathway involved in verapamil metabolism is N-dealkylation via CYP2C8, CYP3A4, and CYP1A2 to the D-617 metabolite. Both norverapamil and D-617 are further metabolized by other CYP isoenzymes to various secondary metabolites. CYP2D6 and CYP2E1 have also been implicated in the metabolic pathway of verapamil, albeit to a minor extent. Minor pathways of verapamil metabolism involve its O-demethylation to D-703 via CYP2C8, CYP2C9, and CYP2C18, and to D-702 via CYP2C9 and CYP2C18. Several steps in verapamil's metabolic pathway show stereoselective preference for the S-enantiomer of the given substrate, including the generation of the D-620 metabolite by CYP3A4/5 and the D-617 metabolite by CYP2C8. Adenosine is eliminated via Adenosine is predominantly eliminated in the urine as uric acid. Verapamil is eliminated via Approximately 70% of an administered dose is excreted as metabolites in the urine and ≥16% in the feces within 5 days. Approximately 3% - 4% is excreted in the urine as unchanged drug. The half-life of Adenosine is The half life of adenosine in blood is less than 10 seconds. The half-life of Verapamil is Single-dose studies of immediate-release verapamil have demonstrated an elimination half-life of 2. 8 to 7. 4 hours, which increases to 4. 5 to 12. 0 hours following repetitive dosing. The elimination half-life is also prolonged in patients with hepatic insufficiency (14 to 16 hours) and in the elderly (approximately 20 hours). Intravenously administered verapamil has rapid distribution phase half-life of approximately 4 minutes, followed by a terminal elimination phase half-life of 2 to 5 hours. The clearance of Adenosine is Data regarding the clearance of adenosine are not readily available. The clearance of Verapamil is Systemic clearance following 3 weeks of continuous treatment was approximately 340 mL/min for R-verapamil and 664 mL/min for S-verapamil. Of note, apparent oral clearance appears to vary significantly between single dose and multiple-dose conditions. The apparent oral clearance following single doses of verapamil was approximately 1007 mL/min for R-verapamil and 5481 mL/min for S-verapamil, whereas 3 weeks of continuous treatment resulted in apparent oral clearance values of approximately 651 mL/min for R-verapamil and 2855 mL/min for S-verapamil. Adenosine toxicity includes Patients experiencing an overdose of adenosine may present with asystole, heart block, or cardiac ischemia; though the effects are generally short lived. Patients experiencing an overdose should be treated with symptomatic and supportive care, which may include a slow intravenous injection of theophylline. The LD 50 in mice is >20 g/kg subcutaneously, 500mg/kg intraperitoneally, and 39. 6 µg/kg subcutaneously. Verapamil toxicity includes Verapamil's reported oral TDLo is 14. 4 mg/kg in women and 3. 429 mg/kg in men. The oral LD 50 is 150 mg/kg in rats and 163 mg/kg in mice. As there is no antidote for verapamil overdosage, treatment is largely supportive. Symptoms of overdose are generally consistent with verapamil's adverse effect profile (i. e. hypotension, bradycardia, arrhythmia) but instances of non-cardiogenic pulmonary edema have been observed following ingestion of large overdoses (up to 9 grams). In acute overdosage, consider the use of gastrointestinal decontamination with cathartics and/or bowel irrigation. Patients presenting with significant myocardial depression may require intravenous calcium, atropine, vasopressors, or other inotropes. Consider the formulation responsible for the overdose prior to treatment - sustained-release formulations may result in delayed pharmacodynamic effects, and these patients should be monitored closely for at least 48 hours following ingestion. Brand names of Adenosine include Adenocard, Viva-drops Lubricating Eye Drops. Brand names of Verapamil include Calan, Isoptin, Tarka, Verelan. No synonyms are available for Adenosine. Adenin riboside Adenine Deoxyribonucleoside Adenogesic Adenosin Adenosina Adénosine Adenosine Adenosinum beta-D-Adenosine No synonyms are available for Verapamil. Adenosine summary: It is Adenosine is a medication used in myocardial perfusion scintigraphy and to treat supraventricular tachycardia. Verapamil summary: It is Verapamil is a non-dihydropyridine calcium channel blocker used in the treatment of angina, arrhythmia, and hypertension. Answer: The subject and the affected drugs are antiarrhythmic drugs with some pro-arrhythmic potentials, such as arrhythmia, QT prolongation, conduction disturbances, and bradycardia. The co-administration of antiarrhythmic agents can result in additive effects and an increased risk of developing these adverse effects.

Adenosine

Drug A is Acenocoumarol. Drug B is Cyclosporine. The severity of the interaction is moderate. The serum concentration of Acenocoumarol can be increased when it is combined with Cyclosporine. The co-administration of warfarin and CYP3A4 inhibitors may cause increased warfarin serum concentrations, which may change INR values and increase the risk of bleeding. The less potent enantiomer of warfarin, R-warfarin, is metabolized by CYP3A4, and therefore its serum concentrations will be increased in the presence of atazanavir, a CYP3A4 inhibitor. S-warfarin is metabolized by CYP2C9, and consequently, it will not interact with CYP3A4 inhibitors. Changes in S-warfarin levels produce more significant changes in warfarin efficacy than do changes in R-warfarin levels. 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. Cyclosporine is indicated for Cyclosporine is approved for a variety of conditions. Firstly, it is approved for the prophylaxis of organ rejection in allogeneic kidney, liver, and heart transplants. It is also used to prevent bone marrow transplant rejection. For the above indications, cyclosporine can be used in conjunction with azathioprine and corticosteroids. Finally, cyclosporine can be used in patients who have chronic transplant rejection and have received previous immunosuppressive therapy and to prevent or treat graft-versus-host disease (GVHD). Secondly, cyclosporine is used for the treatment of patients with severe active rheumatoid arthritis (RA) when they no longer respond to methotrexate alone. It can be used for the treatment of adult non-immunocompromised patients with severe, recalcitrant, plaque psoriasis that have failed to respond to at least one systemic therapy or when systemic therapies are not tolerated or contraindicated. The ophthalmic solution of cyclosporine is indicated to increase tear production in patients suffering from keratoconjunctivitis sicca. In addition, cyclosporine is approved for the treatment of steroid dependent and steroid-resistant nephrotic syndrome due to glomerular diseases which may include minimal change nephropathy, focal and segmental glomerulosclerosis or membranous glomerulonephritis. A cyclosporine ophthalmic emulsion is indicated in the treatment of vernal keratoconjunctivitis in adults and children. Off-label, cyclosporine is commonly used for the treatment of various autoimmune and inflammatory conditions such as atopic dermatitis, blistering disorders, ulcerative colitis, juvenile rheumatoid arthritis, uveitis, connective tissue diseases, as well as idiopathic thrombocytopenic purpura. 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. Cyclosporine pharmacodynamics: Cyclosporine exerts potent immunosuppressive actions on T cells, thereby prolonging survival following organ and bone marrow transplants. This drug prevents and controls serious immune-mediated reactions including allograft rejection, graft versus host disease, and inflammatory autoimmune disease. Some notable effects of cyclosporine are hypertrichosis, gingival hyperplasia, and hyperlipidemia. There is also some debate about this drug causing nephrotoxicity. 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 Cyclosporine is that it Cyclosporine is a calcineurin inhibitor that inhibits T cell activation. Its binding to the receptor cyclophilin-1 inside cells produces a complex known as cyclosporine-cyclophilin. This complex subsequently inhibits calcineurin, which in turn stops the dephosphorylation as well as the activation of the nuclear factor of activated T cells (NF-AT) that normally cause inflammatory reactions. NF-AT is a transcription factor that promotes the production of cytokines such as IL-2, IL-4, interferon-gamma and TNF-alpha, all of which are involved in the inflammatory process. Specifically, the inhibition of IL-2, which is necessary for T cell activation or proliferation, is believed to be responsible for cyclosporine's immunosuppressive actions. In addition to the above, the inhibition of NF-AT leads to lower levels of other factors associated with T helper cell function and thymocyte development. Acenocoumarol absorption: Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration. Cyclosporine absorption: The absorption of cyclosporine occurs mainly in the intestine. Absorption of cyclosporine is highly variable with a peak bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients. The absorption of cyclosporine from the GI tract has been found to be incomplete, likely due to first pass effects. Cmax in both the blood and plasma occurs at approximately 3. 5 hours post-dose. The Cmax of a 0. 1% cyclosporine ophthalmic emulsion is 0. 67 ng/mL after instilling one drop four times daily. A note on erratic absorption During chronic administration, the absorption of Sandimmune Soft Gelatin Capsules and Oral Solution have been observed to be erratic, according to Novartis prescribing information. Those being administered the soft gelatin capsules or oral solution over the long term should be regularly monitored by testing cyclosporine blood concentrations and adjusting the dose accordingly. When compared with the other oral forms of Sandimmune, Neoral capsules and solution have a higher rate of absorption that results in a higher Tmax and a 59% higher Cmax with a 29 % higher 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 Cyclosporine is The distribution of cyclosporine in the blood consists of 33%-47% in plasma, 4%-9% in the lymphocytes, 5%-12% in the granulocytes, and 41%-58% in the erythrocytes. The reported volume of distribution of cyclosporine ranges from 4-8 L/kg. It concentrates mainly in leucocyte-rich tissues as well as tissues that contain high amounts of fat because it is highly lipophilic. Cyclosporine, in the eye drop formulation, crosses the blood-retinal barrier. Acenocoumarol is 98. 7% protein bound, mainly to albumin bound to plasma proteins. Cyclosporine is About 50% of the administered dose is taken up by erythrocytes while about 34% is bound to lipoproteins. Prescribing information for Sandimmune states that 90% is mainly bound to lipoproteins. 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. Cyclosporine metabolism: Cyclosporine is metabolized in the intestine and the liver by CYP450 enzymes, predominantly CYP3A4 with contributions from CYP3A5. The involvement of CYP3A7 is not clearly established. Cyclosporine undergoes several metabolic pathways and about 25 different metabolites have been identified. One of its main active metabolites, AM1, demonstrates only 10-20% activity when compared to the parent drug, according to some studies. The 3 primary metabolites are M1, M9, and M4N, which are produced from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. Acenocoumarol is eliminated via Mostly via the kidney as metabolites. Cyclosporine is eliminated via After sulfate conjugation, cyclosporine remains in the bile where it is broken down to the original compound and then re-absorbed into the circulation. Cyclosporine excretion is primarily biliary with only 3-6% of the dose (including the parent drug and metabolites) excreted in the urine while 90% of the administered dose is eliminated in the bile. From the excreted proportion, under 1% of the dose is excreted as unchanged cyclosporine. The half-life of Acenocoumarol is 8 to 11 hours. The half-life of Cyclosporine is The half-life of cyclosporine is biphasic and very variable on different conditions but it is reported in general to last 19 hours. Prescribing information also states a terminal half-life of approximately 19 hours, but with a range between 10 to 27 hours. No clearance information is available for Acenocoumarol. The clearance of Cyclosporine is Cyclosporin shows a linear clearance profile that ranges from 0. 38 to 3 Lxh/kg, however, there is substantial inter- patient variability. A 250 mg dose of cyclosporine in the oral soft gelatin capsule of a lipid micro-emulsion formulation shows an approximate clearance of 22. 5 L/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. Cyclosporine toxicity includes The oral LD50 in rats is 1480 mg/kg and the TDLO in humans is 12 mg/kg. Overdose information In cases of overdose with oral cyclosporine, forced emesis and gastric lavage are recommended 2 hours after ingestion. There are little data available in the literature regarding overdoses with cyclosporine, but hepatotoxicity and nephrotoxicity may occur. One case report of an cyclosporine overdose due to medical error was made involving a 26 year old female and noted the occurrence of nausea, flushing, tremor, vertigo and vomiting, which resolved within about 1 day. Anorexia and a feeling of increased body girth were also experienced by this patient and resolved within about 2 weeks. When overdose with cyclosporine is observed, it is important to consider that dialysis and charcoal, hemoperfusion are not effective techniques to remove cyclosporine from the body. Brand names of Acenocoumarol include No brand names available. Brand names of Cyclosporine include Cequa, Gengraf, Neoral, Restasis, Sandimmune, Verkazia, Vevye. No synonyms are available for Acenocoumarol. Acénocoumarol Acenocoumarol Acenocoumarolum Acenocumarol Acenocumarolo Acenokumarin Nicoumalone Nicumalon Nitrovarfarian Nitrowarfarin No synonyms are available for Cyclosporine. Ciclosporina Ciclosporine Ciclosporinum Cyclosporin A Cyclosporine 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. Cyclosporine summary: It is Cyclosporine is a steroid-sparing immunosuppressant used in organ and bone marrow transplants as well as inflammatory conditions such as ulcerative colitis, rheumatoid arthritis, and atopic dermatitis. Answer: The co-administration of warfarin and CYP3A4 inhibitors may cause increased warfarin serum concentrations, which may change INR values and increase the risk of bleeding. The less potent enantiomer of warfarin, R-warfarin, is metabolized by CYP3A4, and therefore its serum concentrations will be increased in the presence of atazanavir, a CYP3A4 inhibitor. S-warfarin is metabolized by CYP2C9, and consequently, it will not interact with CYP3A4 inhibitors. Changes in S-warfarin levels produce more significant changes in warfarin efficacy than do changes in R-warfarin levels.

Acenocoumarol

Drug A is Antihemophilic factor (recombinant), PEGylated. Drug B is Doxepin. The severity of the interaction is minor. Doxepin 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. Doxepin is indicated for Oral doxepin is approved for the following indications: Treatment of depression and/or anxiety. Treatment of depression and/or anxiety associated with different conditions, including alcoholism, organic disease and manic-depressive disorders. Treatment of psychotic depressive disorders with associated anxiety. Treatment of involutional depression. Treatment of manic-depressive disorder. Treatment of insomnia characterized by difficulties with sleep maintenance. Topical doxepin is also approved for short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis, pruritus or lichen simplex chronicus. Off-label, doxepin is used topically for the management of neuropathic pain. Depression is a common medical illness that causes feelings of sadness and or loss of interest in prior enjoyable activities. This condition can lead to emotional and physical disturbances that can decrease the ability of a person to function in a regular environment. Anxiety is a normal reaction of the body towards a normal danger. When the anxious state is exacerbated or appears on situations without danger, it is defined as an anxiety disorder. This disorders can appear in different forms such as phobias, panic, obsessive-compulsive disorder and post-traumatic stress disorder. Insomnia is a sleep disorder that directly affects the quality of life of the individual. It is characterized by the complication either to fall asleep or to stay asleep. This condition can be occasional or chronic. Pruritus is defined as an unpleasant skin reaction that provokes the urge to scratch. It can be localized or generalized and it can appear in an acute or chronic manner. Neuropathic pain occurs due to the damage or dysfunction of the peripheral or central nervous system rather than stimulation of the pain receptors. 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,. Doxepin pharmacodynamics: Similar to other tricyclic antidepressants, doxepin was shown, in preclinical trials, to decrease the electrical activity of the brain, prolong the hexobarbital-induced sleep and block avoidance behavior without affecting the conditioned emotional response. At high doses, it also produces symptoms of central nervous system depression. Doxepin is known to cause antidepressant, sedative, and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are the most prevalent which limit its efficacy. These effects are observed at high doses where its affinity for H1 histamine receptor is lost and its binding to other receptors is observed. The maximal antidepressive effects of doxepin are present around two weeks following initiation of therapy. However, the sedative effects of doxepin, usually used for the treatment of insomnia or anxiety, are observed immediately after administration. 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 Doxepin is that it Doxepin exact mechanism of action is not very clear. However, doxepin is known to be a selective histamine H1 receptor blocker. This effect on histamine receptors indicates effectiveness in skin conditions. Breaking its function according to the different effect, doxepin's antidepressive action is primarily associated with the inhibition of the central nervous system biogenic amine reuptake; more specifically, norepinephrine and serotonin at synaptic nerve terminals. This effect increases the level of monoamines in the synaptic site which in order increases the activity at the post-synaptic neuron receptor sites. It has been suggested that doxepin also desensitizes both serotonin 1A receptors and beta-adrenergic receptors. It is known that the lack of dopamine transporters in the frontal cortex and the transmission of dopamine in this region is largely inactivated by the effect of norepinephrine reuptake. Hence, doxepin action on the frontal cortex is suggested to increase dopamine neurotransmission in this area. 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. Doxepin absorption: Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%. The median peak concentration of doxepin ranges from 8. 8-45. 8 ng/ml and it is achieved 3. 5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal. 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 Doxepin is The mean apparent volume of distribution of doxepin is reported to be of 20 L/kg. No protein binding information is available for Antihemophilic factor (recombinant), PEGylated. Doxepin is Equilibrium dialysis indicates a mean protein binding of 75. 5% for doxepin and 76% for desmethyldoxepin. bound to plasma proteins. No metabolism information is available for Antihemophilic factor (recombinant), PEGylated. Doxepin metabolism: Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites. The first-pass metabolism accounts for 55-87% of the administered dose. After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates. The main metabolic enzymes involved in the transformation of doxepin are the members of the cytochrome P450 family, CYP2C19 and CYP2D6 with minor involvement of CYP1A2 and CYP2C9. Antihemophilic factor (recombinant), PEGylated is eliminated via No route of elimination available. Doxepin is eliminated via The elimination profile of doxepin is presented as biphasic. It is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin. 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 Doxepin is The mean elimination half-life is reported to be of 15 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 Doxepin is The mean total apparent plasma clearance of a single oral dose of 50 mg doxepin in healthy individuals is 0. 93 l/hr/kg. Antihemophilic factor (recombinant), PEGylated toxicity includes Common adverse reactions reported in ≥1% of subjects in the clinical studies were headache and nausea. Doxepin toxicity includes Oral LD50 values of doxepin in mouse and rat are 180 mg/kg and 147 mg/kg, respectively. In an overdose state, symptoms of convulsions, dysrhythmias, coma, severe hypotension, central nervous system depression, changes on electrocardiography results and death have been observed. On fertility studies, doxepin was shown to increase the copulatory interval, decrease the corpora lutea, decrease implantation, decreased the number of viable embryos, decrease litter size, increase the number of abnormal sperm and decrease the sperm motility. There is no evidence indicating carcinogenic and mutagenic potential. Brand names of Antihemophilic factor (recombinant), PEGylated include Adynovate. Brand names of Doxepin include Prudoxin, Silenor, Sinequan, Zonalon. No synonyms are available for Antihemophilic factor (recombinant), PEGylated. No synonyms are available for Doxepin. Antihemophilic factor (recombinant), PEGylated summary: It is No summary available. Doxepin summary: It is Doxepin is a psychotropic agent used for the treatment of depression, anxiety, manic-depressive disorder, and 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.

Antihemophilic factor (recombinant), PEGylated

Drug A is Aprotinin. Drug B is Atracurium. The severity of the interaction is minor. The therapeutic efficacy of Atracurium can be decreased when used in combination with Aprotinin. Cholinesterase inhibitors work to increase acetylcholine levels, while anticholinergic agents work to reduce the cholinergic signalling and effects. The concurrent use of a cholinesterase inhibitor and an anticholinergic agent may result in a pharmacodynamic drug-drug interaction, as two agents have opposing mechanisms of action. The literature suggests that the pharmacodynamic drug-drug interaction is more clinically significant than pharmacokinetic interactions, especially in patients with dementia, as they are at risk for developing drug-induced cognitive impairment. By antagonizing each other's pharmacological effect, the anticholinergic agent may antagonize the pharmacological effect of the cholinesterase inhibitor and reduce its therapeutic efficacy. Aprotinin is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion. Atracurium is indicated for No indication available. Aprotinin pharmacodynamics: Aprotinin is a broad spectrum protease inhibitor which modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators [e. g., kallikrein, plasmin] results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation. Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In platelets, aprotinin reduces glycoprotein loss (e. g., GpIb, GpIIb/IIIa), while in granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e. g., CD11b). The effects of aprotinin use in CPB involves a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding. Atracurium pharmacodynamics: No pharmacodynamics available. The mechanism of action of Aprotinin is that it Aprotinin inhibits serine proteases including trypsin, chymotrypsin and plasmin at a concentration of about 125,000 IU/mL, and kallikrein at 300,000 IU/mL. The inhibition of kallikrein inhibits formation of factor XIIa. This inhibits the intrinsic pathway of coagulation and fibrinolysis. Inhibition of plasmin also slows fibrinolysis. The mechanism of action of Atracurium is that it No mechanism of action available. Aprotinin absorption: 100% (IV). No absorption information is available for Atracurium. No volume of distribution information is available for Aprotinin. No volume of distribution information is available for Atracurium. No protein binding information is available for Aprotinin. No protein binding information is available for Atracurium. Aprotinin metabolism: Aprotinin is slowly degraded by lysosomal enzymes. No metabolism information is available for Atracurium. Aprotinin is eliminated via Following a single IV dose of radiolabelled aprotinin, approximately 25-40% of the radioactivity is excreted in the urine over 48 hours. After a 30 minute infusion of 1 million KIU, about 2% is excreted as unchanged drug. After a larger dose of 2 million KIU infused over 30 minutes, urinary excretion of unchanged aprotinin accounts for approximately 9% of the dose. Atracurium is eliminated via No route of elimination available. The half-life of Aprotinin is Following this distribution phase, a plasma half-life of about 150 minutes is observed. At later time points, (i. e., beyond 5 hours after dosing) there is a terminal elimination phase with a half-life of about 10 hours. The half-life of Atracurium is No half-life available. No clearance information is available for Aprotinin. No clearance information is available for Atracurium. No toxicity information is available for Aprotinin. No toxicity information is available for Atracurium. Brand names of Aprotinin include Artiss, Tisseel, Trasylol. Brand names of Atracurium include No brand names available. No synonyms are available for Aprotinin. No synonyms are available for Atracurium. Aprotinin summary: It is Aprotinin is a serine protease inhibitor used to reduce the risk for perioperative blood loss and the need for blood transfusion in high-risk patients during cardiopulmonary bypass for coronary artery bypass graft surgery. Atracurium summary: It is Atracurium is a neuromuscular blocker indicated to relax muscles during mechanical ventilation under general anesthesia or intubation. Answer: Cholinesterase inhibitors work to increase acetylcholine levels, while anticholinergic agents work to reduce the cholinergic signalling and effects. The concurrent use of a cholinesterase inhibitor and an anticholinergic agent may result in a pharmacodynamic drug-drug interaction, as two agents have opposing mechanisms of action. The literature suggests that the pharmacodynamic drug-drug interaction is more clinically significant than pharmacokinetic interactions, especially in patients with dementia, as they are at risk for developing drug-induced cognitive impairment. By antagonizing each other's pharmacological effect, the anticholinergic agent may antagonize the pharmacological effect of the cholinesterase inhibitor and reduce its therapeutic efficacy.

Aprotinin

Drug A is Reteplase. Drug B is Trolamine salicylate. The severity of the interaction is moderate. The risk or severity of bleeding can be increased when Trolamine salicylate is combined with Reteplase. Concurrent use of salicylates and anticoagulants may lead to increased anticoagulant activity and therefore an increased risk of bleeding, due to additive anticoagulant effects. Reteplase is indicated for lysis of acute pulmonary emboli, intracoronary emboli, and management of myocardial infarction. Trolamine salicylate is indicated for Indicated for the temporary relief of aches, and pains of muscles and joints associated with backache, lumbago, strains, bruises, sprains and arthritic or rheumatic pain, pain of tendons and ligaments. Reteplase pharmacodynamics: Reteplase cleaves the Arg/Val bond in plasminogen to form plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. This helps eliminate blood clots or arterial blockages that cause myocardial infarction. Trolamine salicylate pharmacodynamics: Trolamine salicylate is a salicylate that inhibits cyclo-oxygenase (COX) enzymes responsible for generating pro-inflammatory factors such as to induce pain and inflammation. It is thought to mediate its analgesic effect through inhibition of COX-2 enzyme, which is an induced enzyme responsible for inflammatory responses and pain in muscle and joint disorders. By inhibiting fatty acid COX enzyme, trolamine salicylate inhibits the production of prostaglandins and thromboxanes in inflammatory cells involved in generating pain and inflammation. It thereby works to temporarily reduce mild to moderate pain. In subjects with muscle soreness from exercise, administration of topical trolamine salicylate was associated with reduced duration and severity of muscule soreness compared to placebo. In subjects with osteoarthritis in hands, trolamine salicylate cream was shown to be effective in achieving temporary relief of minor pain and stiffness. The mechanism of action of Reteplase is that it Reteplase binds to fibrin rich clots via the fibronectin finger-like domain and the Kringle 2 domain. The protease domain then cleaves the Arg/Val bond in plasminogen to form plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. The mechanism of action of Trolamine salicylate is that it Inflammation and tissue damage in different conditions including arthritis, bursitis, joint disorder, bruises, and strains or sprains of muscle origin, induce mild to moderate pain and are associated with increase prostaglandin synthesis. This is thought to be a result of COX-2 enzyme induction. COX-2 is induced in inflammatory cells in case of cell injury, infection or activation from inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α. Upon activation, COX-2 produces prostanoid mediators of inflammation such as prostaglandins and thromboxanes. Trolamine salicylate mediates its analgesic effect by inhibiting the production of inflammatory mediators that sensitize nociceptive nerve endings and generate pain. No absorption information is available for Reteplase. Trolamine salicylate absorption: Following topical administration of 10% trolamine salicylate in healthy volunteers, salicylic acid could not be detected in serum indicating low systemic absorption. No volume of distribution information is available for Reteplase. The volume of distribution of Trolamine salicylate is Topical administration of 1 gram of 10% trolamine salicylate in abdominal rat skin resulted in an approximate extravascular volume of distribution (V/F) of 24. 0 mL. No protein binding information is available for Reteplase. No protein binding information is available for Trolamine salicylate. No metabolism information is available for Reteplase. No metabolism information is available for Trolamine salicylate. Reteplase is eliminated via No route of elimination available. Trolamine salicylate is eliminated via Following topical administration of 10% trolamine salicylate in healthy volunteers, urinary recovery of total salicylate during the first 24 hours was 6. 9 mg (p < 0. 05), which is 1. 4% of total dose. The half-life of Reteplase is No half-life available. The half-life of Trolamine salicylate is No half-life available. No clearance information is available for Reteplase. No clearance information is available for Trolamine salicylate. No toxicity information is available for Reteplase. Trolamine salicylate toxicity includes It is hazardous in case of ingestion. The carcinogenicity, mutagenicity and effects on reproductive fertility of trolamine salicylate have not been reported. Brand names of Reteplase include Retavase. Brand names of Trolamine salicylate include Asper-flex, Aspercreme, Mobisyl, Myoflex, Sportscreme. No synonyms are available for Reteplase. No synonyms are available for Trolamine salicylate. Reteplase summary: It is Reteplase is a purified form of human tissue plasminogen activator used in the emergency treatment of myocardial infarction, ischemic stroke, and pulmonary emboli. Trolamine salicylate summary: It is Trolamine salicylate is a medication used to relieve minor aches and pains of the muscles and joints. Answer: . Concurrent use of salicylates and anticoagulants may lead to increased anticoagulant activity and therefore an increased risk of bleeding, due to additive anticoagulant effects.

Reteplase

Drug A is Anakinra. Drug B is Chlorpheniramine. The severity of the interaction is moderate. The metabolism of Chlorpheniramine 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 CYP2D6 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. Chlorpheniramine is indicated for the treatment of rhinitis, urticaria, allergy, common cold, asthma and hay fever. 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. Chlorpheniramine pharmacodynamics: 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. Chlorpheniramine, is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It competes with histamine for the normal H 1 -receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. 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 Chlorpheniramine is that it Chlorpheniramine binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. 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. Chlorpheniramine absorption: Well absorbed in the gastrointestinal tract. 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. No volume of distribution information is available for Chlorpheniramine. No protein binding information is available for Anakinra. Chlorpheniramine is 72% bound to plasma proteins. Anakinra metabolism: As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body. Chlorpheniramine metabolism: Primarily hepatic via Cytochrome P450 (CYP450) enzymes. 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. Chlorpheniramine 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 Chlorpheniramine is 21-27 hours. 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. No clearance information is available for Chlorpheniramine. 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. Chlorpheniramine toxicity includes Oral LD50 (rat): 306 mg/kg; Oral LD50 (mice): 130 mg/kg; Oral LD50 (guinea pig): 198 mg/kg [Registry of Toxic Effects of Chemical Substances. Ed. D. Sweet, US Dept. of Health & Human Services: Cincinatti, 2010. ]. Also a mild reproductive toxin to women of childbearing age. Brand names of Anakinra include Kineret. Brand names of Chlorpheniramine include Aller-chlor, Allerest PE, Children's Nyquil Cold and Cough, Codar Ar, Coricidin Hbp Cold & Flu, Coricidin Hbp Cough and Cold, Dimetapp Long Acting Cough Plus Cold, Robitussin Pediatric Cough & Cold LA, Scot-tussin Sugar Free DM, Sudogest, Tussicaps, Tussionex, Tuxarin, Tuzistra. No synonyms are available for Anakinra. No synonyms are available for Chlorpheniramine. Chlorphenamin Chlorphenamine Chlorphenaminum Chlorpheniramine polistirex Chlorpheniraminum Clorfenamina Clorfeniramina 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). Chlorpheniramine summary: It is Chlorpheniramine is a histamine-H1 receptor antagonist indicated for the management of symptoms associated with upper respiratory allergies. 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 CYP2D6 substrates.

Anakinra

Drug A is Corifollitropin alfa. Drug B is Lithium citrate. The severity of the interaction is minor. Lithium citrate may decrease the excretion rate of Corifollitropin alfa 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. Corifollitropin alfa is indicated for Controlled ovarian stimulation in cases of women who are undergoing fertility treatment to stimulate the development of more than one mature egg simultaneously in the ovaries in combination with a gonadotrophin-releasing hormone (GnRH) antagonist (a type of medicine also used in fertility treatments). Lithium citrate is indicated for Lithium is used as a mood stabilizer, and is used for treatment of depression and mania. It is often used in bipolar disorder treatment. Corifollitropin alfa pharmacodynamics: A single dose of corifollitropin alfa could initiate and sustain multi-follicular growth in patients undergoing controlled ovarian stimulation, such as during in vitro fertilization or intracytoplasmic sperm injection. This drug is structurally similar to follicle stimulating hormone (FSH), a hormone naturally present in females. FSH stimulates the production of eggs (ova) in the ovaries. In corifollitropin alfa, a peptide is attached to the FSH to prolong its activity. As a result, one single dose of the medicine can be administered to stimulate egg production for seven days, replacing daily injections that are normally needed with other FSH medicines. In phase III clinical trials, the number of oocytes retrieved following the administration of corifollitropin alfa was slightly higher compared with the number observed with daily recombinant FSH treatment. Lithium citrate pharmacodynamics: Although lithium has been used for over 50 years in treatment of bipolar disorder, the mechanism of action is still unknown. Lithium's therapeutic action may be due to a number of effects, ranging from inhibition of enzymes such as glycogen synthase kinase 3, inositol phosphatases, or modulation of glutamate receptors. The mechanism of action of Corifollitropin alfa is that it Corifollitropin alfa is a long-lasting single injection fusion protein which lacks luteinizing hormone (LH) activity. Only one injection is needed for the first 7 days, which replaces the first 7 daily injections of traditional follicle stimulating hormone (FSH). It is a follicle-stimulation hormone (human α-subunit reduced), a combination of follicle stimulation hormone (human β-subunit reduced) fusion protein with 118-145-chorionic gonadotropin (human β-subunit). Frequent, repetitive injections increase stress and error rates, and are often a burden for women, leading to therapy noncompliance. The agent comprises an alpha-subunit, which is identical to that of FSH, and a beta-subunit, which is produced by the fusion of the C-terminal peptide from the beta-subunit of chorionic gonadotropin to the beta-subunit of FSH. Corifollitropin alfa serves as a sustained follicle stimulant that has similar pharmacological effects to recombinant follicle stimulating hormone (rFSH), however, with a relatively long elimination half-life, resulting in a longer duration of action. This is achieved using site-directed mutagenesis and gene transfer techniques to create a glycoprotein that consists of an α-subunit that is identical to human follicle stimulating hormone (FSH) noncovalently bound to a β-subunit comprised of a complete β-chain of human FSH elongated by the carboxyterminal peptide of the β-subunit of human chorionic gonadotrophin (hCG). This unit interacts with the FSH receptor to stimulate the release of oocytes. Corifollitropin alfa does not demonstrate any intrinsic LH/hCG activity. The mechanism of action of Lithium citrate is that it The precise mechanism of action of Li+ as a mood-stabilizing agent is currently unknown. It is possible that Li+ produces its effects by interacting with the transport of monovalent or divalent cations in neurons. An increasing number of scientists have come to the conclusion that the excitatory neurotransmitter glutamate is the key factor in understanding how lithium works. Lithium has been shown to change the inward and outward currents of glutamate receptors (especially GluR3), without a shift in reversal potential. Lithium has been found to exert a dual effect on glutamate receptors, acting to keep the amount of glutamate active between cells at a stable, healthy level, neither too much nor too little. It is postulated that too much glutamate in the space between neurons causes mania, and too little, depression. Another mechanism by which lithium might help to regulate mood include the non-competitive inhibition of an enzyme called inositol monophosphatase. Alternately lithium's action may be enhanced through the deactivation of the GSK-3B enzyme. The regulation of GSK-3B by lithium may affect the circadian clock. GSK-3 is known for phosphorylating and thus inactivating glycogen synthase. GSK-3B has also been implicated in the control of cellular response to damaged DNA. GSK-3 normally phosphorylates beta catenin, which leads to beta catenin degratation. When GSK-3 is inhibited, beta catenin increases and transgenic mice with overexpression of beta catenin express similar behaviour to mice treated with lithium. These results suggest that increase of beta catenin may be a possible pathway for the therapeutic action of lithium. Corifollitropin alfa absorption: After one single subcutaneous injection of this drug, the maximal serum concentration is 4. 24 ng/mL (2. 49-7. 21 ng/mL1) and is reached 44 hours (35-57 h) post-dose administration. Its absolute bioavailability is 58% (48-70%). No absorption information is available for Lithium citrate. The volume of distribution of Corifollitropin alfa is Distribution, metabolism and elimination of corifollitropin alfa are very similar to other gonadotropins, such as FSH, hCG and LH. After absorption into the blood, corifollitropin alfa is distributed mainly to the ovaries and the kidneys. The steady-state volume of distribution is 9. 2 L. Exposure to corifollitropin alfa increases in a linear fashion with the dose within a range of 60 micrograms - 240 micrograms. No volume of distribution information is available for Lithium citrate. No protein binding information is available for Corifollitropin alfa. No protein binding information is available for Lithium citrate. Corifollitropin alfa metabolism: The metabolic fate of corifollitropin alfa highly resembles that of endogenous glycoprotein hormones, which predominantly is comprised of kidney clearance and the urinary excretion of the intact protein in parallel to kidney catabolism. No metabolism information is available for Lithium citrate. Corifollitropin alfa is eliminated via Radioactivity labeling showed that the drug was mainly (86%) excreted in the urine. 90% of the radioactivity in serum was identified as [(125)I]corifollitropin alfa, but only 7-15% of the radioactivity in urine was identified as [(125)I]corifollitropin alfa and its dissociation products, the alpha- and beta-subunits (including its CTP part). Elimination of corifollitropin alfa mainly occurs via the kidneys. The elimination rate of this drug may be reduced in patients with renal insufficiency. Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa. Lithium citrate is eliminated via No route of elimination available. The half-life of Corifollitropin alfa is Corifollitropin alfa has a longer half-life compared with FSH and thus requires less frequent dosing. Corifollitropin alfa has an elimination half-life of 70 hours (59-82 hours). The half-life of Lithium citrate is No half-life available. The clearance of Corifollitropin alfa is 0. 13 L/h (0. 10-0. 18 L/h1). No clearance information is available for Lithium citrate. Corifollitropin alfa toxicity includes The most common side effects with Elonva (seen in between 1 and 10 patients in 100) include a headache, nausea, fatigue, pelvic pain and/or discomfort, breast tenderness and ovarian hyperstimulation syndrome (OHSS). This syndrome occurs when the ovaries have a heightened response to therapy, leading to abdominal swelling and pain, nausea and diarrhea. More than one injection of Elonva within one treatment cycle or an excessively high dose of Elonva and/or (rec)FSH can increase the risk of ovarian hyperstimulation syndrome, which may cause swollen or painful ovaries, abdominal bloating, nausea, and a weight gain of up to 3kg. In severe cases, ovarian hyperstimulation syndrome may cause rapid weight gain ranging from 15 to 20 kilograms in 5-10 days. Severe abdominal pain, severe, persistent nausea, and vomiting, decreased urination, and abdominal bloating, as well as other generalized symptoms, may occur. About 1 - 2 % of women undergoing ovarian stimulation develop a severe form of ovarian hyperstimulation syndrome (OHSS). Severe OHSS can be life-threatening. Complications may include: ascites, pulmonary edema, electrolyte disturbances (sodium, potassium, others), thrombosis in large vessels, usually in the lower extremities, renal failure, ovarian torsion, rupture of ovarian cysts. Some of these conditions can lead to hemorrhage, respiratory failure, spontaneous miscarriage or pregnancy termination due to complications, resulting in death. No toxicity information is available for Lithium citrate. Brand names of Corifollitropin alfa include Elonva. Brand names of Lithium citrate include No brand names available. No synonyms are available for Corifollitropin alfa. No synonyms are available for Lithium citrate. Corifollitropin alfa summary: It is Corifollitropin alfa is a FSH analogue indicated for Controlled Ovarian Stimulation (COS) in combination with a GnRH antagonist for the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) program. Lithium citrate summary: It is No summary available. 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.

Corifollitropin alfa

Drug A is Aldesleukin. Drug B is Iloperidone. The severity of the interaction is moderate. The metabolism of Iloperidone can be decreased when combined with Aldesleukin. Iloperidone is metabolized by CYP3A4, and therefore, the concomitant administration of a CYP3A4 inhibitor will reduce the metabolism and increase the serum concentration of iloperidone. Elevated serum levels of iloperidone may also increase the risk of iloperidone adverse effects. A study investigating the interaction between iloperidone and strong CYP3A4 inhibitor ketoconazole (400mg daily for 4 days) found that this combination increased the AUC of iloperidone and its active metabolite by 57% and 55% respectively. Aldesleukin is indicated for treatment of adults with metastatic renal cell carcinoma. Iloperidone is indicated for Treatment of acute schizophrenia. 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. Iloperidone pharmacodynamics: Iloperidone shows high affinity and maximal receptor occupancy for dopamine D2 receptors in the caudate nucleus and putamen of the brains of schizophrenic patients. The improvement in cognition is attributed to iloperidone's high affinity for α adrenergic receptors. Iloperidone also binds with high affinity to serotonin 5-HT2a and dopamine 3 receptors. Iloperidone binds with moderate affinity to dopamine D4, serotonin 5-HT6 and 5-HT7, and norepinephrine NEα1 receptors. Furthermore, iloperidone binds with weak affinity to serotonin 5-HT1A, dopamine D1, and histamine H1 receptors. 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 Iloperidone is that it Iloperidone is a dopamine D2 and 5-HT2A receptor antagonist and acts as a neuroleptic agent. No absorption information is available for Aldesleukin. Iloperidone absorption: Well absorbed from the GI tract and Cmax is reached within 2-4 hours. Steady-state concentration is achieved in 3-4 days post-administration of iloperidone. Relative bioavailability of the tablet formulation compared to oral solution is 96%. Accumulation occurs in a predictable fashion. The volume of distribution of Aldesleukin is 0. 18 l/kg. The volume of distribution of Iloperidone is Apparent Vd = 1340-2800 L. No protein binding information is available for Aldesleukin. Iloperidone is 95% of iloperidone is bound to protein. Percent bound is not altered by renal or hepatic impairment or combination therapy with ketoconazole. bound to plasma proteins. No metabolism information is available for Aldesleukin. Iloperidone metabolism: Iloperidone is hepatically metabolized by cytochrome enzymes which mediates O-dealkylation (CYP3A4), hydroxylation (CYP2D6), and decarboxylation/reduction processes. Metabolites formed are P89, P95, and P88. The minor metabolite is P89, whereas P95 and P88 are the major ones. The affinity of the iloperidone metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3. 91) and the NEα1A, NEα1B, NEα1D, and NEα2C receptors (Ki values of 4. 7, 2. 7, 8. 8 and 4. 7 nM respectively). 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. Iloperidone is eliminated via Renal (in which <1% of iloperidone is excreted unchanged). The half-life of Aldesleukin is 13 min-85 min. The half-life of Iloperidone is The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26 and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37 and 31 hours, respectively. No clearance information is available for Aldesleukin. The clearance of Iloperidone is Apparent clearance (clearance/bioavilability) = 47-102 L/h. No toxicity information is available for Aldesleukin. Iloperidone toxicity includes Commonly observed adverse reactions (incidence ≥5% and two-fold greater than placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased. Brand names of Aldesleukin include Proleukin. Brand names of Iloperidone include Fanapt. No synonyms are available for Aldesleukin. No synonyms are available for Iloperidone. Iloperidone Ilopéridone Iloperidonum 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. Iloperidone summary: It is Iloperidone is an atypical antipsychotic agent used for the acute treatment of schizophrenia in adults. Answer: Iloperidone is metabolized by CYP3A4, and therefore, the concomitant administration of a CYP3A4 inhibitor will reduce the metabolism and increase the serum concentration of iloperidone. Elevated serum levels of iloperidone may also increase the risk of iloperidone adverse effects. A study investigating the interaction between iloperidone and strong CYP3A4 inhibitor ketoconazole (400mg daily for 4 days) found that this combination increased the AUC of iloperidone and its active metabolite by 57% and 55% respectively.

Aldesleukin

Drug A is Bupivacaine. Drug B is Gepirone. The severity of the interaction is moderate. The risk or severity of CNS depression can be increased when Bupivacaine is combined with Gepirone. 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. 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. Gepirone is indicated for Gepirone is indicated for the treatment of major depressive disorder (MDD) in adults. 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. Gepirone pharmacodynamics: The pharmacological activity of gepirone is attributed to the parent drug and its major metabolites 3’-OH-gepirone and 1-. PP. Gepirone and its 3’-OH metabolite bind to 5HT 1A receptors (K i = 38 nM and 58 nM, respectively), where they act as agonists, while the 1-PP metabolite binds to α 2 receptors (K i = 42 nM). In a thorough QT study, the largest mean increase in baseline- and placebo-corrected QTc interval with administration of 100 mg per day immediate-release formulation of gepirone was 18. 4 msec (upper 90% confidence interval [CI] = 22. 7 ms) on Day 1 and 16. 1 msec (upper 90% CI = 20. 7 ms) on Day 7. The exposure in this study was 2-fold the exposure of the maximum recommended dose. 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 Gepirone is that it The mechanism of the antidepressant effect of gepirone is not fully understood but is thought to be related to its modulation of serotonergic activity in the CNS through selective agonist activity at 5HT 1a receptors. Particularly, gepirone. 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. Gepirone absorption: The pharmacokinetics of gepirone are linear and dose-proportional from 18. 2 mg to 72. 6 mg. Steady-state plasma concentrations are typically achieved within two to four days of daily dosing. The absolute bioavailability is 14% to 17%. The maximal plasma gepirone concentration (Cmax ) after dosing is reached within 6 hours post-dose (Tmax ). After a high-fat meal, Tmax is reached at 3 hours. A significant effect of food has been observed on the peak plasma concentration (Cmax ) of gepirone and, to a lesser extent, on the total exposure (AUC 0-t last, AUC 0-∞ ) to gepirone. The magnitude of the food effect was dependent of the fat content of the meal. The systemic exposure of gepirone and major metabolites was consistently higher under fed conditions as compared to the fasted state. Gepirone Cmax after intake of a low-fat (~ 200 calories) breakfast was 27% higher, after medium-fat (~500 calories) breakfast 55% higher, and after a high-fat (~ 850 calories) breakfast 62% higher as compared to the fasted state. The AUC after intake of a low-fat breakfast was about 14% higher, after a medium-fat breakfast 22% higher, and after a high-fat breakfast 32 to 37% higher as compared to the fasted state. The effect of varying amounts of fat on Cmax and AUC of the major metabolites 3-OH-gepirone and 1PP were similar to that found for gepirone. No volume of distribution information is available for Bupivacaine. The volume of distribution of Gepirone is The apparent volume of distribution of gepirone is approximately 94. 5L. Bupivacaine is Bupivacaine is ~95% protein bound. bound to plasma proteins. Gepirone is The in vitro plasma protein binding in humans is 72% and is not concentration-dependent. The in vitro plasma protein binding for metabolite 3’-OH gepirone is 59% and 42% for 1-PP. 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. Gepirone metabolism: Gepirone is extensively metabolized and both major metabolites 1-PP and 3’-OH-gepirone are present in plasma in higher concentrations than the parent compound. CYP3A4 is the primary enzyme catalyzing the metabolism of EXXUA to its major pharmacologically active metabolites. Bupivacaine is eliminated via Only 6% of bupivacaine is excreted unchanged in the urine. Gepirone is eliminated via Following a single oral dose of [ C]-labeled gepirone, approximately 81% and 13% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. 60% of the gepirone was eliminated in the urine within the first 24 hours. The presence of hepatic or renal impairment did affect the apparent clearance of gepirone. 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 Gepirone is The mean terminal half-life is approximately 5 hours. No clearance information is available for Bupivacaine. The clearance of Gepirone is After the administration of 80 mg of gepirone, the apparent clearance of gepirone and its 2 metabolites, 1-PP and 3’-OH-gepirone, was calculated to be 692 ± 804 L/h, 417 ± 249 L/h, and 146 ± 61. 7 L/h respectively. 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. Gepirone toxicity includes In embryo-fetal development studies, oral administration of gepirone to pregnant rats (75, 150, and 300 mg/kg) or pregnant rabbits (50, 100, and 200 mg/kg) during the period of organogenesis resulted in decreased embryofetal growth, body weights, and lengths, with accompanying skeletal variations at mid and high doses; the mid doses are 18 and 24 times the maximum recommended human dose (MRHD) on a mg/m basis in rats and rabbits, respectively. No malformations were seen in these studies. The developmental no observed adverse effect level (NOAEL) was 9 and 12 times the MRHD on a mg/m2 basis in rats and rabbits, respectively. When pregnant rats were treated with gepirone (10, 20, and 40 mg/kg) from late gestation through weaning, decreased birth weights were seen at mid and high doses; the mid-dose is twice the MRHD. Increased offspring mortality during the first 4 days after birth and persistent reduction in body weight were observed at all doses; the lowest dose is approximately equal to the MRHD on a mg/m basis. The no-effect dose for fetal effects was not determined in this study. When gepirone was administered orally to male and female rats prior to and throughout mating, gestation, and lactation at doses of 5, 27, 64, and 150 mg/kg/day, increased stillbirths were seen at ≥64 mg/kg. Early postnatal mortality was increased at 150 mg/kg (18 times the MRHD on a mg/m basis). The NOAEL (27 mg/kg) for stillbirths was associated with a maternal dose 3 times the MRHD on a mg/m basis. Fetal weights were decreased at 27 mg/kg (3 times the MRHD on a mg/m2 basis) and fetal lengths were decreased at 64 mg/kg (8 times the MRHD on a mg/m basis) and above. Pup weights were decreased at birth, throughout lactation and weaning, and until at least 14 weeks of age, with delays of some developmental landmarks, at 64 mg/kg and above. The NOAEL for growth and development (5 mg/kg) was associated with a maternal dose below the MRHD on a mg/m2 basis. In the pediatric trial patients, there was a higher occurrence of vomiting in pediatric patients (13%) compared to adults (6. 6%). Antidepressants, such as gepirone, increase the risk of suicidal thoughts and behaviors in pediatric patients. In clinical studies, cases of acute ingestions of up to 454 mg (6. 25 times the maximum recommended dose) of gepirone alone or in combination with other drugs, were reported. Signs and symptoms reported with an overdose of gepirone at doses up to 454 mg included vomiting and transient incomplete bundle branch block; an unknown dose of gepirone produced an altered level of consciousness and a 60-second convulsion. No specific antidotes for gepirone are known. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations. No evidence of carcinogenic potential was observed in lifetime carcinogenicity studies performed in rats and mice at doses up to 43. 6 and 317. 8 mg/kg/day, respectively. These doses are approximately 6 and 18 times the MRHD, respectively, on a mg/m basis. Gepirone showed no mutagenicity in three different in vitro genotoxicity assays (bacterial gene mutation, mammalian gene mutation, or DNA repair). No clastogenicity was observed in a rat micronucleus assay. When gepirone was administered orally to male and female rats prior to and throughout mating at daily doses of 5, 27, 64, and 150 mg/kg, the latency to mating was increased at doses of 64 mg/kg (8 times the MRHD on a mg/m basis) and above. 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 Gepirone include Exxua. No synonyms are available for Bupivacaine. Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine No synonyms are available for Gepirone. Bupivacaine summary: It is Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures. Gepirone summary: It is Gepirone is a serotonin receptor agonist used to treat major depressive disorder in adults. 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.

Bupivacaine

Drug A is Ocrelizumab. Drug B is Pentostatin. The severity of the interaction is major. Ocrelizumab may increase the immunosuppressive activities of Pentostatin. Co-administration of ocrelizumab with other immune-modulating or immunosuppressive agents may lead to immunosuppression, increasing the risk of serious infection. Ocrelizumab is indicated for Ocrelizumab is a CD20-directed cytolytic antibody indicated for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Ocrelizumab is also indicated for the treatment of primary progressive MS in adults. Pentostatin is indicated for the treatment of hairy cell leukaemia refractory to alpha interferon. Ocrelizumab pharmacodynamics: Since ocrelizumab interferes with the CD20 assay, CD19+B-cells are used to assess B-cell counts after treatment. Fourteen days following infusion, a reduction in CD19+B-cell counts was observed. In clinical studies, B-cell counts rose above the lower limit of normal (LLN) or baseline counts between infusions of ocrelizumab at least once in 0. 3% to 4. 1% of patients. In a clinical study involving 51 patients, the time for B-cell counts to return to baseline or LLN ranged from 27 to 125 weeks, with a median time of 72 weeks after the last infusion. Within 2. 5 years after the last infusion, B-cell counts returned to either baseline or LNN in 90% of patients treated with ocrelizumab. Since ocrelizumab is a recombinant humanized antibody, it is expected to be less immunogenic than rituximab, a chimeric antibody. Compared to the ocrelizumab pivotal trial, a rituximab phase II trial had a higher proportion of anti-drug antibodies, suggesting greater immunogenicity. However, caution should be exercised since these studies used different assay methods, and the association between anti-drug antibody development and infusion reactions has not been fully elucidated. The use of ocrelizumab can cause infusion reactions, and lead to a higher risk of respiratory tract infections and viral infections. Cases of progressive multifocal leukoencephalopathy (PML) and immune-mediated colitis have been reported in patients treated with ocrelizumab. Also, an increased risk of malignancy may exist. Pentostatin pharmacodynamics: Pentostatin is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia and hairy cell leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Cytotoxicity is cell cycle phase-specific (S-phase). The mechanism of action of Ocrelizumab is that it Ocrelizumab is a recombinant humanized antibody that targets CD20, a glycosylated phosphoprotein expressed on the surface of different types of B-cells. CD20 can be found on pre-B cells, naïve and memory B-cells, and it is not expressed on hematopoietic stem B-cells, pro-B cells (precursors), or differentiated plasma cells. Therefore, by targeting CD20, ocrelizumab does not affect the concentration of IgG and IgM antibodies in blood or the cerebrospinal fluid. B-cells contribute to the pathogenesis of multiple sclerosis (MS) through the activation of proinflammatory T-cells and the secretion of proinflammatory cytokines. Also, B-cells may differentiate into plasma cells that produce autoantibodies directed against myelin, leading to the complement-mediated attack on the myelin sheath. By targeting CD20, ocrelizumab specifically depletes B-cells. While the exact mechanism of ocrelizumab leading to B-cell depletion is unknown, there are several proposed mechanisms. It has been suggested that upon cell surface binding to CD20-expressing B-cells, ocrelizumab promotes antibody-dependent cellular cytotoxicity and complement-mediated cell lysis while preserving the capacity for B-cell reconstitution and preexisting humoral immunity. The mechanism of action of Pentostatin is that it Pentostatin is a potent transition state inhibitor of adenosine deaminase (ADA), the greatest activity of which is found in cells of the lymphoid system. T-cells have higher ADA activity than B-cells, and T-cell malignancies have higher activity than B-cell malignancies. The cytotoxicity that results from prevention of catabolism of adenosine or deoxyadenosine is thought to be due to elevated intracellular levels of dATP, which can block DNA synthesis through inhibition of ribonucleotide reductase. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Cytotoxicity is cell cycle phase-specific (S-phase). Ocrelizumab absorption: Ocrelizumab displays a two-compartment pharmacokinetic model with time-dependent clearance. The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of ocrelizumab was 3,510 mcg/mL per day. Following the intravenous infusion of maintenance doses of 600 mg every 6 months in relapsing MS patients, the mean peak plasma concentration of ocrelizumab (Cmax ) was 212 mcg/mL. Following intravenous infusion of two 300 mg doses separated by 14 days every 6 months in patients with PPMS, Cmax was 141 mcg/mL. Ocrelizumab follows linear and dose proportional pharmacokinetics between 400 mg and 2000 mg. Pentostatin absorption: Not absorbed orally, crosses blood brain barrier. The volume of distribution of Ocrelizumab is In a population pharmacokinetic estimate, the central volume of distribution of ocrelizumab was 2. 78 L. No volume of distribution information is available for Pentostatin. No protein binding information is available for Ocrelizumab. Pentostatin is 4% bound to plasma proteins. Ocrelizumab metabolism: As with other antibodies, ocrelizumab is expected to undergo nonspecific catabolism and broken into smaller peptides and amino acids. Pentostatin metabolism: Primarily hepatic, but only small amounts are metabolized. Ocrelizumab is eliminated via Monoclonal antibodies (mAb) such as ocrelizumab are too large to be filtered by the kidneys, and therefore, not eliminated in urine under normal conditions. If antibody fragments of low molecular weight are filtered, they are usually reabsorbed and metabolized in the proximal tubule. The peptides and amino acids produced by catabolism are recycled or used as an energy source. Pentostatin is eliminated via In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity. The half-life of Ocrelizumab is The terminal elimination half-life of ocrelizumab was 26 days. The half-life of Pentostatin is 5. 7 hours (with a range between 2. 6 and 16 hrs). The clearance of Ocrelizumab is The constant clearance of ocrelizumab was 0. 17 L/day, while the initial time-dependent clearance was 0. 05 L/day. Peripheral volume and inter-compartment clearance were 2. 68 L and 0. 29 L/day, respectively. The clearance of Pentostatin is 68 mL/min/m2. Ocrelizumab toxicity includes Toxicity information regarding ocrelizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as immune-mediated colitis. Symptomatic and supportive measures are recommended. The carcinogenic and mutagenic potentials of ocrelizumab have not been evaluated. In monkeys given three loading doses of 15 or 75 mg/kg intravenously, followed by weekly doses of 20 or 100 mg/kg for 8 weeks (2-10 times the recommended human dose), ocrelizumab did not have effects on reproductive organs. No reproductive effects were detected on the estrus cycle of female monkeys given the same ocrelizumab regimen. Pentostatin toxicity includes LD 50 =128 mg/kg (mouse), side effects include lethargy, rash, fatigue, nausea and myelosuppression. Brand names of Ocrelizumab include Ocrevus. Brand names of Pentostatin include Nipent. No synonyms are available for Ocrelizumab. No synonyms are available for Pentostatin. Ocrelizumab summary: It is Ocrelizumab is a CD20 specific monoclonal antibody used to treat relapsing remitting multiple sclerosis. Pentostatin summary: It is Pentostatin is an adenosine deaminase inhibitor used to treat hairy cell leukemia. Answer: Co-administration of ocrelizumab with other immune-modulating or immunosuppressive agents may lead to immunosuppression, increasing the risk of serious infection.

Ocrelizumab

Drug A is Antihemophilic factor, human recombinant. Drug B is Danaparoid. The severity of the interaction is major. The therapeutic efficacy of Antihemophilic factor, human recombinant can be decreased when used in combination with Danaparoid. 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. Antihemophilic factor, human recombinant is indicated for The human recombinant antihemophilic factor is indicated for use in adults and children with hemophilia A for the control and prevention of bleeding episodes, perioperative management, and routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Danaparoid is indicated for Indicated for the prophylaxis of post-operative deep venous thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing elective hip replacement surgery. Antihemophilic factor, human recombinant pharmacodynamics: Antihemophilic Factor binds factor IXa along with calcium and phospholipid, This complex converts factor X to factor Xa to facilitate clotting cascade. Danaparoid pharmacodynamics: Danaparoid contains a mixture of heparan sulfate, dermatan sulfate and chondroitin sulfate in amounts of approximately 84%, 12% and 4%, respectively. Danaparoid is as an antithrombotic agent that prevents the formation of fibrin in the coagulation pathway. It has a high antifactor Xa to antifactor IIa (thrombin) activity that primarily works via antithrombin III-mediated inhibition of factor Xa. The ratio of antifactor Xa to antifactor II activity is ≥ 20:1. Danaparoid has a minor effect on platelet function and aggregation. In a worldwide compassionate-use programme involving a total of 667 patients with heparin-induced thrombocytopenia (HIT), treatment with danaparoid resulted in 93% of successful outcomes in resolving HIT. In healthy volunteers, danaparoid caused significantly less prolongation o f the activated partial thromboplastin time (APTT) and was associated with a significantly lower thrombin time than unfractionated heparin (UFH) and low molecular weight heparins (LMWHs). Danaparoid displays lower lipolytic activity than UFH in vitro and in healthy individuals, leading to lower plasma levels of free fatty acids. Danaparoid has been associated with the cross-reactivity with pathogenic heparin-induced platelet-factor 4 (PF4) antibodies, which occurs in about 10 % or more by in vitro testing. The clinical relevance of this effect is not fully understood. The mechanism of action of Antihemophilic factor, human recombinant is that it Antihemophilic factor (AHF) is a protein found in normal plasma which is necessary for clot formation. The administration of AHF provides an increase in plasma levels of AHF and can temporarily correct the coagulation defect of patients with hemophilia A (classical hemophilia). The mechanism of action of Danaparoid is that it In the coagulation cascade leading to clot formation, factor X and factor II requires activation to promote subsequent conversion of fibrinogen to fibrin. The mechanism of action of danaparoid resulting in anticoagulant and antithrombic effects involves a complex interaction between 2 components, factor IIa and in particular, factor Xa. Via binding to antithrombin and inducing a conformational change, danaparoid enhances and catalyzes the binding of factor Xa to antithrombin, which induces antithrombin-mediated inactivation of factor Xa. This leads to inhibition of thrombin generation and subsequently, thrombus formation. Danaparoid also weakly enhances antithrombin III and heparin cofactor II inactivation of factor IIa. There is evidence that danaparoid also suppresses the activation of factor IX which, in conjunction with simultaneous inhibition of factor X, may lead to antithrombic effects. No absorption information is available for Antihemophilic factor, human recombinant. Danaparoid absorption: Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly antifactor Xa and antifactor IIa activities. The bioavailability of danaparoid is 100% following subcutaneous administration. Following administration of single subcutaneous doses of 750, 1500, 2250, and 3250 anti-Xa units of danaparoid, the peak plasma anti-Xa activities were 102. 4, 206. 1, 283. 9, and 403. 4 mU/mL, respectively. The time to reach maximum anti-Xa activity is approximately 2-5 hours. No volume of distribution information is available for Antihemophilic factor, human recombinant. The volume of distribution of Danaparoid is Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. The volumes of distribution of anti-Xa and anti-IIa activities are 9. 1 L and 7. 3-9. 0 L, respectively. No protein binding information is available for Antihemophilic factor, human recombinant. No protein binding information is available for Danaparoid. No metabolism information is available for Antihemophilic factor, human recombinant. Danaparoid metabolism: There is no evidence of hepatic metabolism and danaparoid is unlikely to undergo cellular metabolism. Antihemophilic factor, human recombinant is eliminated via No route of elimination available. Danaparoid is eliminated via Renal excretion is the main route of elimination, accounting for approximately 40-50% of the total clearance of antifactor Xa activity following intravenous administration of danaparoid. Therefore in patients with severe renal impairment, the elimination half-life of anti-Xa activity may be prolonged. The half-life of Antihemophilic factor, human recombinant is 8. 4-19. 3 hrs. The half-life of Danaparoid is Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. The elimination half-life ranges from 19. 2 to 24. 5 hours during anti-Xa activity and ranges from 1. 8 to 4. 3 hours during anti-IIa activity. The clearance of Antihemophilic factor, human recombinant is 4. 1 mL/h•kg [Previously treated pediatric patients]. The clearance of Danaparoid is Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. Total plasma clearance is about 0. 36 L/h during anti-Xa activity, which may be accelerated with higher body surface area. Total plasma clearance during anti-IIa activity ranges from 2. 3 to 3 L. No toxicity information is available for Antihemophilic factor, human recombinant. Danaparoid toxicity includes Subcutaneous administration of a single dose at 3800 anti-Xa units/kg, which is 20. 5 times the recommended dose for humans based on body surface area, was found to be lethal to female rats. Lethal effects were seen in male rats when administering a single subcutaneous dose at 15200 anti-Xa units/kg, which is approximately 82 times the recommended human dose based on body surface area. In rats, the symptoms of acute toxicity following intravenous administration included respiratory depression, prostration and twitching. Accidental overdosage of danaparoid may lead to severe bleeding complications. While protamine sulfate may partially neutralize the anti-Xa actions of danaparoid, there is no evidence that it is capable of reducing severe non-surgical bleeding during treatment of danaparoid. In case of serious bleeding, danaparoid should be discontinued and blood transfusions should be administered if necessary. Withdrawal of danaparoid is expected to restore the coagulation balance without rebound phenomenon. There is no evidence of danaparoid to have a potential to induce carcinogenesis, mutagenesis and impairment of fertility. Brand names of Antihemophilic factor, human recombinant include Advate, Adynovate, Helixate, Kogenate, Kovaltry, Novoeight, Recombinate. Brand names of Danaparoid include Orgaran. No synonyms are available for Antihemophilic factor, human recombinant. No synonyms are available for Danaparoid. Antihemophilic factor, human recombinant summary: It is Antihemophilic factor, human recombinant is a form of recombinant coagulation Factor VIII used to treat hemophilia A, von Willebrand disease, and Factor XIII deficiency. Danaparoid summary: It is Danaparoid is a heparinoid with anticoagulant and antithrombotic activities used for the treatment of acute episode of Heparin-Induced Thrombocytopenia (HIT), and for prophylaxis in patients with a history of HIT. 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.

Antihemophilic factor, human recombinant

Drug A is Rituximab. Drug B is Betaxolol. The severity of the interaction is moderate. Betaxolol 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. Betaxolol is indicated for the management of 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. Betaxolol pharmacodynamics: Betaxolol is a competitive, beta(1)-selective (cardioselective) adrenergic antagonist. Betaxolol is used to treat hypertension, arrhythmias, coronary heart disease, glaucoma, and is also used to reduce non-fatal cardiac events in patients with heart failure. Activation of beta(1)-receptors (located mainly in the heart) by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Drugs such as betaxolol that block these receptors therefore have the reverse effect: they lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, beta(1)-selective blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. Betaxolol is lipophilic and exhibits no intrinsic sympathomimetic activity (ISA) or membrane stabilizing activity. 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 Betaxolol is that it Betaxolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Betaxolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm. 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). Betaxolol absorption: Absorption of an oral dose is complete. There is a small and consistent first-pass effect resulting in an absolute bioavailability of 89% ± 5% that is unaffected by the concomitant ingestion of food or alcohol. 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). No volume of distribution information is available for Betaxolol. Rituximab is Not available. bound to plasma proteins. Betaxolol is 50% bound to plasma proteins. Rituximab metabolism: As a monoclonal antibody, rituximab is expected to be metabolized by proteases throughout the body. Betaxolol metabolism: Primarily hepatic. Approximately 15% of the dose administered is excreted as unchanged drug, the remainder being metabolites whose contribution to the clinical effect is negligible. 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. Betaxolol is eliminated via No route of elimination available. 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 Betaxolol is 14-22 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). No clearance information is available for Betaxolol. 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. Betaxolol toxicity includes Oral LD 50 s are 350 to 400 mg betaxolol/kg in mice and 860 to 980 mg/kg in rats. Predicted symptoms of overdose include bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. Brand names of Rituximab include MabThera, Riabni, Rituxan, Rituxan Hycela, Ruxience, Truxima. Brand names of Betaxolol include Betoptic, Betoptic Pilo, Betoptic S. No synonyms are available for Rituximab. No synonyms are available for Betaxolol. Bétaxolol Betaxololum 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. Betaxolol summary: It is Betaxolol is a cardioselective beta blocking agent commonly used to treat hypertension and elevated intraocular pressure (when administered ophthalmically). 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 Botulinum toxin type B. Drug B is Dexbrompheniramine. The severity of the interaction is moderate. The risk or severity of CNS depression can be increased when Botulinum toxin type B is combined with Dexbrompheniramine. 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. Botulinum toxin type B is indicated for the treatment of patients with cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia. Dexbrompheniramine is indicated for treatment and relief of symptoms of allergies, hay fever, and colds. Botulinum toxin type B pharmacodynamics: Botulinum Toxin Type B inhibits acetylcholine release at the neuromuscular junction via a three stage process: 1) Heavy Chain mediated neurospecific binding of the toxin, 2) internalization of the toxin by receptor-mediated endocytosis, and 3) ATP and pH dependent translocation of the Light Chain to the neuronal cytosol where it acts as a zinc-dependent endoprotease cleaving polypeptides essential for neurotransmitter release. Dexbrompheniramine pharmacodynamics: 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. Dexbrompheniramine 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. The mechanism of action of Botulinum toxin type B is that it Botulinum Toxin Type B binds to and cleaves the synaptic Vesicle Associated Membrane Protein (VAMP, also known as synaptobrevin) which is a component of the protein complex responsible for docking and fusion of the synaptic vesicle to the presynaptic membrane, a necessary step to neurotransmitter release. The mechanism of action of Dexbrompheniramine is that it Dexbrompheniramine competitively binds to the histamine H 1 -receptor. It competes with histamine for the normal H 1 -receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. Botulinum toxin type B absorption: Though pharmacokinetic or ADME studies were not performed, Botulinum Toxin Type B is not expected to be present in the peripheral blood at measurable levels following IM injection at the recommended doses. Dexbrompheniramine absorption: Antihistamines are well absorbed from the gastrointestinal tract after oral administration. No volume of distribution information is available for Botulinum toxin type B. No volume of distribution information is available for Dexbrompheniramine. No protein binding information is available for Botulinum toxin type B. No protein binding information is available for Dexbrompheniramine. No metabolism information is available for Botulinum toxin type B. Dexbrompheniramine metabolism: Hepatic (cytochrome P-450 system), some renal. Botulinum toxin type B is eliminated via No route of elimination available. Dexbrompheniramine is eliminated via No route of elimination available. The half-life of Botulinum toxin type B is No half-life available. The half-life of Dexbrompheniramine is 25 hours. No clearance information is available for Botulinum toxin type B. No clearance information is available for Dexbrompheniramine. Botulinum toxin type B toxicity includes One unit of Botulinum Toxin Type B corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice. Dexbrompheniramine toxicity includes Signs of an overdose include fast or irregular heartbeat, mental or mood changes, tightness in the chest, and unusual tiredness or weakness. Brand names of Botulinum toxin type B include Myobloc. Brand names of Dexbrompheniramine include Ala-hist Ir, Ala-hist PE, Dologen, Dologesic Reformulated Jun 2016. No synonyms are available for Botulinum toxin type B. No synonyms are available for Dexbrompheniramine. Desbrofeniramina Dexbromfeniramina Dexbrompheniramin Dexbromphéniramine Dexbrompheniramine Dexbrompheniraminum Botulinum toxin type B summary: It is Botulinum toxin type B is a purified form of botulinum toxin type B used to block acetylcholine release in the treatment of cervical dystonia and sialorrhea. Dexbrompheniramine summary: It is Dexbrompheniramine is an antihistamine used to treat allergy symptoms including upper respiratory tract symptoms. 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.

Botulinum toxin type B

Drug A is Obinutuzumab. Drug B is Halothane. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Halothane is combined with Obinutuzumab. 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. Obinutuzumab is indicated for Obinutuzumab is used as a combination treatment with chlorambucil to treat patients with untreated chronic lymphocytic leukemia. Halothane is indicated for the induction and maintenance of general anesthesia. Obinutuzumab pharmacodynamics: Obinutuzumab is more potent than rituximab in depleting B-cells, antitumor activity, and tumor regression. Halothane pharmacodynamics: Halothane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It reduces the blood pressure and frequently decreases the pulse rate and depresses respiration. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. 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 Halothane is that it Halothane causes general anaethesia due to its actions on multiple ion channels, which ultimately depresses nerve conduction, breathing, cardiac contractility. Its immobilizing effects have been attributed to its binding to potassium channels in cholinergic neurons. Halothane's effect are also likely due to binding to NMDA and calcium channels, causing hyperpolarization. Obinutuzumab absorption: Obinutuzumab is administered intravenously, so its absorption is 100%. No absorption information is available for Halothane. The volume of distribution of Obinutuzumab is Obinutuzumab has a volume of distribution of about 3. 8 L. No volume of distribution information is available for Halothane. Obinutuzumab is Obinutuzumab does not bind to plasma proteins. bound to plasma proteins. No protein binding information is available for Halothane. Obinutuzumab metabolism: Obinutuzumab is not metabolized by the liver. Halothane metabolism: Halothane is metabolized in the liver, primarily by CYP2E1, and to a lesser extent by CYP3A4 and CYP2A6. Obinutuzumab is eliminated via The route of elimination of obinutuzumab was not indicated (FDA label). Halothane is eliminated via No route of elimination available. The half-life of Obinutuzumab is The half life of obinutuzumab is 28. 4 days. The half-life of Halothane is No half-life available. The clearance of Obinutuzumab is The clearance of obinutuzumab is 0. 09L/day. No clearance information is available for Halothane. 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. Halothane toxicity includes Toxic effects of halothane include malignant hyperthermia and hepatitis. Brand names of Obinutuzumab include Gazyva. Brand names of Halothane include No brand names available. No synonyms are available for Obinutuzumab. No synonyms are available for Halothane. Bromochlorotrifluoroethane Halotano Halothane Halothanum Obinutuzumab summary: It is Obinutuzumab is an antineoplastic CD20 antibody used to treat untreated chronic lymphocytic leukemia in combination with chlorambucil. Halothane summary: It is Halothane is a general inhalation anesthetic used for the induction and maintenance of general anesthesia. 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.

Obinutuzumab