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Drug A is Bumetanide. Drug B is Captopril. The severity of the interaction is moderate. The excretion of Captopril can be decreased when combined with Bumetanide. Organic anion transporter 3 (OAT3) is responsible for the excretion of a wide variety of drugs, toxins, and metabolites in the kidney, liver, and other tissues. Inhibitors of this transporter attenuates the drug efflux, leading to increased serum concentrations of OAT3 substrates. Co-administration of OAT3 inhibitors with OAT3 substrates, and resulting elevating systemic exposure to those substrates, may alter the clinical efficacy of drug therapy and increase the risk for developing drug-related adverse reactions. Bumetanide is indicated for the treatment of edema associated with congestive heart failure, hepatic and renal disease including the nephrotic syndrome. Captopril is indicated for the treatment of essential or renovascular hypertension (usually administered with other drugs, particularly thiazide diuretics). May be used to treat congestive heart failure in combination with other drugs (e. g. cardiac glycosides, diuretics, β-adrenergic blockers). May improve survival in patients with left ventricular dysfunction following myocardial infarction. May be used to treat nephropathy, including diabetic nephropathy. Bumetanide pharmacodynamics: Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in patients in whom high doses of furosemide are ineffective. There is however no reason not to use bumetanide as a first choice drug. The main difference between the two substances is in bioavailability. Bumetanide has more predictable pharmacokinetic properties as well as clinical effect. In patients with normal renal function, bumetanide is 40 times more effective than furosemide. Captopril pharmacodynamics: Captopril, an ACE inhibitor, antagonizes the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain its effects by causing increased vasodilation and decreased blood pressure. The mechanism of action of Bumetanide is that it Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. The mechanism of action of Captopril is that it There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Captopril, one of the few ACE inhibitors that is not a prodrug, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Captopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. Captopril’s affinity for ACE is approximately 30,000 times greater than that of ATI. Bumetanide absorption: Bumetanide is completely absorbed (80%), and the absorption is not altered when taken with food. Bioavailability is almost complete. Captopril absorption: 60-75% in fasting individuals; food decreases absorption by 25-40% (some evidence indicates that this is not clinically significant). No volume of distribution information is available for Bumetanide. No volume of distribution information is available for Captopril. Bumetanide is 97% bound to plasma proteins. Captopril is 25-30% bound to plasma proteins, primarily albumin bound to plasma proteins. Bumetanide metabolism: 45% is secreted unchanged. Urinary and biliary metabolites are formed by oxidation of the N-butyl side chain. Captopril metabolism: Hepatic. Major metabolites are captopril-cysteine disulfide and the disulfide dimer of captopril. Metabolites may undergo reversible interconversion. Bumetanide is eliminated via Oral administration of carbon-14 labeled Bumex to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Biliary excretion of Bumex amounted to only 2% of the administered dose. Captopril is eliminated via No route of elimination available. The half-life of Bumetanide is 60-90 minutes. The half-life of Captopril is 2 hours. The clearance of Bumetanide is 0. 2 - 1. 1 mL/min/kg [preterm and full-term neonates with respiratory disorders]. 2. 17 mL/min/kg [neonates receiving bumetanide for volume overload] 1. 8 +/- 0. 3 mL/min/kg [geriatric subjects] 2. 9 +/- 0. 2 mL/min/kg [younger subjects] No clearance information is available for Captopril. Bumetanide toxicity includes Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels. Captopril toxicity includes Symptoms of overdose include emesis and decreased blood pressure. Side effects include dose-dependent rash (usually maculopapular), taste alterations, hypotension, gastric irritation, cough, and angioedema. Brand names of Bumetanide include Bumex, Burinex. Brand names of Captopril include No brand names available. No synonyms are available for Bumetanide. Bumetanide Bumetanidum No synonyms are available for Captopril. Captoprilum Captopryl L-Captopril Bumetanide summary: It is Bumetanide is a sulfamyl diuretic used to treat edema in congestive heart failure, hepatic and renal disease, and nephrotic syndrome. Captopril summary: It is Captopril is an ACE inhibitor used for the management of essential or renovascular hypertension, congestive heart failure, left ventricular dysfunction following myocardial infarction, and nephropathy. Answer: Organic anion transporter 3 (OAT3) is responsible for the excretion of a wide variety of drugs, toxins, and metabolites in the kidney, liver, and other tissues. Inhibitors of this transporter attenuates the drug efflux, leading to increased serum concentrations of OAT3 substrates. Co-administration of OAT3 inhibitors with OAT3 substrates, and resulting elevating systemic exposure to those substrates, may alter the clinical efficacy of drug therapy and increase the risk for developing drug-related adverse reactions.

Bumetanide

Drug A is Acarbose. Drug B is Propranolol. The severity of the interaction is moderate. The therapeutic efficacy of Acarbose can be increased when used in combination with Propranolol. Diabetic patients taking beta blockers are 1. 27 times more likely to develop hypoglycemia than those not taking beta blockers. 1 Acarbose is indicated for Acarbose is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Propranolol is indicated for Propranolol is indicated to treat hypertension. Propranolol is also indicated to treat angina pectoris due to coronary atherosclerosis, atrial fibrillation, myocardial infarction, migraine, essential tremor, hypertrophic subaortic stenosis, pheochromocytoma, and proliferating infantile hemangioma. Acarbose pharmacodynamics: Acarbose is a complex oligosaccharide that competitively inhibits the ability of brush-border alpha-glucosidase enzymes to break down ingested carbohydrates into absorbable monosaccharides, reducing carbohydrate absorption and subsequent postprandial insulin levels. Acarbose requires the co-administration of carbohydrates in order to exert its therapeutic effect, and as such should be taken with the first bite of a meal three times daily. Given its mechanism of action, acarbose in isolation poses little risk of contributing to hypoglycemia - this risk is more pronounced, however, when acarbose is used in conjunction with other antidiabetic therapies (e. g. sulfonylureas, insulin). Patients maintained on acarbose in addition to other antidiabetic agents should be aware of the symptoms and risks of hypoglycemia and how to treat hypoglycemic episodes. There have been rare post-marketing reports of the development of pneumatosis cystoides intestinalis following treatment with alpha-glucosidase inhibitors - patients experiencing significant diarrhea/constipation, mucus discharge, and/or rectal bleeding should be investigated and, if pneumatosis cystoides intestinalis is suspected, should discontinue therapy. Propranolol pharmacodynamics: Propranolol is a beta-adrenergic receptor antagonist used to treat hypertension. Propranolol has a long duration of action as it is given once or twice daily depending on the indication. When patients abruptly stop taking propranolol, they may experience exacerbations of angina and myocardial infarctions. The mechanism of action of Acarbose is that it Alpha-glucosidase enzymes are located in the brush-border of the intestinal mucosa and serve to metabolize oligo-, tri-, and disaccharides (e. g. sucrose) into smaller monosaccharides (e. g. glucose, fructose) which are more readily absorbed. These work in conjunction with pancreatic alpha-amylase, an enzyme found in the intestinal lumen that hydrolyzes complex starches to oligosaccharides. Acarbose is a complex oligosaccharide that competitively and reversibly inhibits both pancreatic alpha-amylase and membrane-bound alpha-glucosidases - of the alpha-glucosidases, inhibitory potency appears to follow a rank order of glucoamylase > sucrase > maltase > isomaltase. By preventing the metabolism and subsequent absorption of dietary carbohydrates, acarbose reduces postprandial blood glucose and insulin levels. The mechanism of action of Propranolol is that it Propranolol is a nonselective β-adrenergic receptor antagonist. Blocking of these receptors leads to vasoconstriction, inhibition of angiogenic factors like vascular endothelial growth factor (VEGF) and basic growth factor of fibroblasts (bFGF), induction of apoptosis of endothelial cells, as well as down regulation of the renin-angiotensin-aldosterone system. Acarbose absorption: The oral bioavailability of acarbose is extremely minimal, with less than 1-2% of orally administered parent drug reaching the systemic circulation. Despite this, approximately 35% of the total radioactivity from a radiolabeled and orally administered dose of acarbose reaches the systemic circulation, with peak plasma radioactivity occurring 14-24 hours after dosing - this delay is likely reflective of metabolite absorption rather than absorption of the parent drug. As acarbose is intended to work within the gut, its minimal degree of oral bioavailability is therapeutically desirable. Propranolol absorption: Patients taking doses of 40mg, 80mg, 160mg, and 320mg daily experienced Cmax values of 18±15ng/mL, 52±51ng/mL, 121±98ng/mL, and 245±110ng/mL respectively. Propranolol has a Tmax of approximately 2 hours, though this can range from 1 to 4 hours in fasting patients. Taking propranolol with food does not increase Tmax but does increase bioavailability. No volume of distribution information is available for Acarbose. The volume of distribution of Propranolol is The volume of distribution of propranolol is approximately 4L/kg or 320L. Acarbose is As only 1-2% of an orally administered dose is absorbed into the circulation, acarbose is unlikely to be subject to clinically relevant protein binding. bound to plasma proteins. Propranolol is Approximately 90% of propranolol is protein bound in plasma. Other studies have reported ranges of 85-96%. bound to plasma proteins. Acarbose metabolism: Acarbose is extensively metabolized within the gastrointestinal tract, primarily by intestinal bacteria and to a lesser extent by digestive enzymes, into at least 13 identified metabolites. Approximately 1/3 of these metabolites are absorbed into the circulation where they are subsequently renally excreted. The major metabolites appear to be methyl, sulfate, and glucuronide conjugates of 4-methylpyrogallol. Only one metabolite - resulting from the cleavage of a glucose molecule from acarbose - has been identified as having alpha-glucosidase inhibitory activity. Propranolol metabolism: Propranolol undergoes side chain oxidation to α-naphthoxylactic acid, ring oxidation to 4’-hydroxypropranolol, or glucuronidation to propranolol glucuronide. It can also be N-desisopropylated to become N-desisopropyl propranolol. 17% of a dose undergoes glucuronidation and 42% undergoes ring oxidation. Acarbose is eliminated via Roughly half of an orally administered dose is excreted in the feces within 96 hours of administration. What little drug material is absorbed into the systemic circulation (approximately 34% of an orally administered dose) is excreted primarily by the kidneys, suggesting renal excretion would be a significant route of elimination if the parent drug was more readily absorbed - this is further supported by data in which approximately 89% of an intravenously administered dose of acarbose was excreted in the urine as active drug (in comparison to <2% following oral administration) within 48 hours. Propranolol is eliminated via 91% of an oral dose of propranolol is recovered as 12 metabolites in the urine. The half-life of Acarbose is In healthy volunteers, the plasma elimination half-life of acarbose is approximately 2 hours. The half-life of Propranolol is The elimination half-life of propranolol is approximately 8 hours. The plasma half-life of propranolol is 3 to 6 hours. No clearance information is available for Acarbose. The clearance of Propranolol is The clearance of propranolol is 2. 7±0. 03L/h/kg in infants <90 days and 3. 3±0. 35L/h/kg in infants >90 days. Propranolol clearance increases linearly with hepatic blood flow. Propranolol has a clearance in hypertensive adults of 810mL/min. Acarbose toxicity includes The symptoms of acarbose overdose are likely to be consistent with its adverse effect profile and may therefore include significant gastrointestinal (GI) symptoms (flatulence, distension, etc), although an overdose on an empty stomach (i. e. when not co-administered with food) is less likely to result in these GI symptoms. In the event of an overdose, patients should be instructed to avoid carbohydrate-containing foods for 4-6 hours following administration as these can precipitate the aforementioned GI symptoms. Propranolol toxicity includes Symptoms of overdose include hypotension, hypoglycemic seizure, restlessness, euphoria, insomnia. Patients with asthma may develop bronchospasm. In case of overdose, monitor vital signs, mental status, and blood glucose. Treat hypotension with intravenous fluids, bradycardia with atropine, and isoproterenol and aminophylline for bronchospasm. If patients do not respond to intravenous fluids, follow up with glucagon 50-150µg/kg intravenously, then 1-5mg/hour, followed by catecholamines. Dialysis will not be useful as propranolol is highly protein bound. Brand names of Acarbose include Precose. Brand names of Propranolol include Hemangeol, Hemangiol, Inderal, Innopran. No synonyms are available for Acarbose. No synonyms are available for Propranolol. Propanalol Propanolol Propranolol Propranololo Propranololum Acarbose summary: It is Acarbose is an alpha-glucosidase inhibitor used in adjunctly with diet and exercise for the management of glycemic control in patients with type 2 diabetes mellitus. Propranolol summary: It is Propranolol is a non-selective beta adrenergic antagonist used to treat hypertension, angina, atrial fibrillation, myocardial infarction, migraine, essential tremor, hypertrophic subaortic stenosis, and pheochromocytoma. Answer: Diabetic patients taking beta blockers are 1. 27 times more likely to develop hypoglycemia than those not taking beta blockers.

Acarbose

Drug A is Reslizumab. Drug B is Natalizumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Natalizumab is combined with Reslizumab. 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. Reslizumab is indicated for Indicated for the add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype. 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. Reslizumab pharmacodynamics: A reduction in blood eosinophil counts was observed in clinical studies following an initial infusion of 3 mg/kg reslizumab and was maintained through 52 weeks of treatment with no signs of tachyphylaxis. Greater reductions of blood eosinophils were observed in subjects with higher reslizumab serum concentrations. This effect was independent of the presence of treatment-emergent anti-reslizumab antibodies. 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 Reslizumab is that it Reslizumab an interleukin-5 (IL-5) antagonist (IgG4, kappa) that binds to IL-5 with a dissociation constant of 81 pM. IL-5 is a proinflammatory cytokine responsible for the terminal maturation of eosinophils and increases chemotaxis, endothelial adhesion, activation and survival of eosinophils. Eosinophils are known to play a central role in the pathophysiology of many patients with asthma; upon activation, eosinophils release leukotrienes, platelet activation factor, major basic protein, eosinophil cationic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and other cytokines that are cytotoxic to the bronchial epithelium and lead to airway inflammation and bronchospasm. IL-5 production is increased by upon activation of TH2 lymphocytes after antigen exposure and IL-5 stimulates the production and maturation of eosinophil precursors in the bone marrow. IL-5 promotes the growth and differentiation, recruitment, activation, and survival of eosinophils via interacting with the IL-5 receptor expressed on the eosinophil surface. Increased production and activation of eosinophils is especially prominent in nonallergic forms of asthma. Reslizumab is a humanized monoclonal antibody that occupies the region ERRR (glutamic acid, arginine, arginine, arginine) corresponding to amino acids 89–92 on IL-5, which is a region critical for its interaction with the IL-5 receptor on the eosinophil surface. By binding to IL-5 and disrupting its binding to the alpha chain of the IL-5 receptor complex, reslizumab inhibits the bioactivity of IL-5 and attenuates IL-5 signaling. Blocking of IL-5 signalling thereby reduces the production and survival of eosinophils and inhibits eosinophilic-driven inflammation. 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. Reslizumab absorption: The peak serum concentrations of reslizumab were typically observed at the end of the infusion with the serum concentrations gradually declining from the peak in a biphasic manner. Following multiple doses, serum concentrations of reslizumab accumulated approximately 1. 5 to 1. 9-fold. Interindividual variability in peak and overall exposure across healthy individuals, patients with asthma, and other populations in pharmacokinetic studies was around 20-30%. Systemic exposure to reslizumab appeared to be unaffected by the presence of treatment-emergent anti-reslizumab antibodies. 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 Reslizumab is The approximate volume of distribution of reslizumab is 5L, suggesting minimal distribution to the extravascular tissues. 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 Reslizumab. Natalizumab is No information is available. bound to plasma proteins. Reslizumab metabolism: Like other monoclonal antibodies, reslizumab is assumed to undergo enzymatic proteolysis into smaller peptides and amino acids. As reslizumab bind to the target, it is not expected to undergo a target-mediated clearance. Natalizumab metabolism: No information is available. Reslizumab is eliminated via No route of elimination available. Natalizumab is eliminated via No information is available. The half-life of Reslizumab is The half-life is approximately 24 days. 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 Reslizumab is Reslizumab clearance was approximately 7 mL/hour. 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. Reslizumab toxicity includes Single doses of up to 732 mg have been administered intravenously to subjects in clinical trials without evidence of dose-related toxicities. There is no specific treatment for an overdose with reslizumab. If the event of an overdose, the patient should be treated supportively with appropriate monitoring as necessary. Based on the findings of a 6-month bioassay, reslizumab showed no evidence of carcinogenicity. In a fertility study, administration of reslizumab to parental mice at doses up to 50 mg/kg. (approximately 6 times the MRHD on an AUC basis) had no effects on male or female mating or fertility. The malignancy risk of reslizumab in humans with effects on tumor growth is not yet established. 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 Reslizumab include Cinqair. Brand names of Natalizumab include Tysabri. No synonyms are available for Reslizumab. No synonyms are available for Natalizumab. Reslizumab summary: It is Reslizumab is an IL-5 antagonist used as an add-on maintenance treatment of patients with severe eosinophilic asthma in adults. Natalizumab summary: It is Natalizumab is a monoclonal anti-integrin antibody used to treat Crohn's disease or multiple sclerosis. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Reslizumab

Drug A is Adalimumab. Drug B is Cobimetinib. The severity of the interaction is major. The metabolism of Cobimetinib can be increased when combined with Adalimumab. The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. Adalimumab is indicated for Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. Cobimetinib is indicated for Cobimetinib is indicated in combination with vemurafenib for the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. As a single agent, cobimetinib is also indicated for the treatment of adult patients with histiocytic neoplasms. 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. Cobimetinib pharmacodynamics: Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase 1 (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a BRAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases. Cobimetinib is used in combination with vemurafenib because the clinical benefit of a BRAF inhibitor is limited by intrinsic and acquired resistance. Reactivation of the MAPK pathway is a major contributor to treatment failure in BRAF-mutant melanomas, approximately ~80% of melanoma tumors become BRAF-inhibitor resistant due to reactivation of MAPK signaling. BRAF-inhibitor-resistant tumor cells are sensitive to MEK inhibition, therefore cobimetinib and vemurafenib will result in dual inhibition of BRAF and its downstream target, MEK. 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 Cobimetinib is that it Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E and K mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. In mice implanted with tumor cell lines expressing BRAF V600E, cobimetinib inhibited tumor cell growth. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of cobimetinib and vemurafenib resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model. 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. Cobimetinib absorption: Following oral dosing of 60 mg once daily in cancer patients, the median time to achieve peak plasma levels (Tmax ) was 2. 4 (range:1–24) hours, geometric mean steady-state AUC₀–₂₄h was 4340 ng∙h/mL (61% CV) and Cmax was 273 ng/mL (60% CV). The absolute bioavailability of COTELLIC was 46% (90% CI: 40%, 53%) in healthy subjects. A high‐fat meal (comprised of approximately 150 calories from protein, 250 calories from carbohydrate, and 500–600 calories from fat) had no effect on cobimetinib AUC and Cmax after a single 20 mg COTELLIC was administered to healthy subjects. The volume of distribution of Adalimumab is The distribution volume (Vss) ranged from 4. 7 to 6. 0 L following intravenous administration of doses ranging from 0. 25 to 10 mg/kg in RA patients. The volume of distribution of Cobimetinib is The estimated apparent volume of distribution was 806 L in cancer patients based on a population PK analysis. No protein binding information is available for Adalimumab. Cobimetinib is Cobimetinib is 95% bound to human plasma proteins in vitro, independent of drug concentration. bound to plasma proteins. No metabolism information is available for Adalimumab. Cobimetinib metabolism: Cobimetinib is mainly metabolized via CYP3A oxidation and UGT2B7 glucuronidation with no major metabolites formed. Adalimumab is eliminated via Adalimumab is most likely removed by opsonization via the reticuloendothelial system. Cobimetinib is eliminated via Following oral administration of a single 20 mg radiolabeled cobimetinib dose, 76% of the dose was recovered in the feces (with 6. 6% as unchanged drug) and 17. 8% of the dose was recovered in the urine (with 1. 6% as unchanged drug). 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 Cobimetinib is Following oral administration of COTELLIC 60 mg once daily in cancer patients, the mean elimination half-life (t1/2) was 44 (range: 23–70) 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 Cobimetinib is Following oral administration of COTELLIC 60 mg once daily in cancer patients, the mean apparent clearance (CL/F) was 13. 8 L/h (61% CV). 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. Cobimetinib toxicity includes The most common adverse effects (>20%) for cobimetinib are diarrhea, photosensitivity reactions, nausea, fever and vomiting. Brand names of Adalimumab include Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry. Brand names of Cobimetinib include Cotellic. No synonyms are available for Adalimumab. No synonyms are available for Cobimetinib. 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. Cobimetinib summary: It is Cobimetinib is an antineoplastic agent and selective inhibitor of the mitogen-activated extracellular kinase (MEK) pathway used to treat unresectable or metastatic melanoma. Answer: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index.

Adalimumab

Drug A is Acetazolamide. Drug B is Fluocinolone acetonide. The severity of the interaction is moderate. Acetazolamide may increase the excretion rate of Fluocinolone acetonide 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. Fluocinolone acetonide is indicated for Fluocinolone acetonide has been used extensively in different medical areas. -In dermatology, it is extensively used for the relief of inflammatory dermatosis, dermatitis, psoriasis, hypertrophic tissues, keloid tissues and atopic dermatitis. -It has been used in shampoo products as a low to medium potency corticosteroid for the treatment of seborrheic dermatitis of the scalp. -In ear drops, it is used as a low to medium potency corticosteroid for the treatment of chronic eczematous external otitis in adults and pediatric patients 2 years and older. -As an intravitreal implant, it is indicated for the treatment of diabetic macular edema with patients that have been previously treated with a course of corticosteroids and no clinically significant rise in intraocular pressure. -Fluocinolone acetonide was announced on October 15, 2018 to be FDA approved for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye. -Some reports have indicated the use of fluocinolone acetonide as a vasoprotective agent and for its use in the treatment of first-degree hemorrhoids. 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. Fluocinolone acetonide pharmacodynamics: Fluocinolone acetonide is a synthetic anti-inflammatory corticosteroid and thus, the effect of its interaction with the body produces vasoconstriction and suppression of membrane permeability, mitotic activity, immune response and release of inflammatory mediators. For its ophthalmic indications, fluocinolone acetonide is administered as intravitreal micro-insert. This preparation was observed in clinical trials to reduce the recurrence of uveitis flares by 2 fold when compared with the non treated patients even after six months after initial administration. As well the intraocular pressure seemed to increase slightly with the presence of the fluocinolone implant but it is important to monitor intraocular pressure. 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 Fluocinolone acetonide is that it Fluocinolone acetonide is a corticosteroid and thus, it can be inferred that it acts by inhibiting the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, collagen deposition, and scar formation. Some reports have indicated that fluocinolone acetonide presents a high binding affinity for the glucocorticoid receptor. After binding the receptor, the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements in the promoter region of the target genes. This effect promotes the induction of phospholipase A2 inhibitory proteins (lipocortins). Through this mechanism of action, it is thought that fluocinolone induces mainly one of the lipocortins, annexin 1, which will later mediate the synthesis of inflammatory mediators such as prostaglandins and leukotrienes by inhibiting the release of arachidonic acid which is the precursor of all these inflammatory mediators. Hence, the induction of these proteins will prevent the release of arachidonic acid by phospholipase A2. No absorption information is available for Acetazolamide. Fluocinolone acetonide absorption: When administered as an eye implant, fluocinolone acetonide presents a sustained delivery for even 12 months in which there can be observed a sustained release. The concentration of fluocinolone acetonide are generally higher in the vitreous and retina with a little dispersion to the aqueous humor. There are reports indicating that topical administration of fluocinolone acetonide produces a percutaneous absorption which is determined by the vehicle, integrity of the epidermal barrier and the use of occlusive dressing. Independently of the route of administration, the systemic absorption of fluocinolone acetonide is below 0. 1 ng/ml which indicates that the systemic distribution is very minimal and the effect of fluocinolone is mainly local. No volume of distribution information is available for Acetazolamide. The volume of distribution of Fluocinolone acetonide is This pharmacokinetic parameter is not relevant as the systemic absorption of fluocinolone acetonide is very minimal. Acetazolamide is 98% bound to plasma proteins. Fluocinolone acetonide is This pharmacokinetic parameter is not relevant as the systemic absorption of fluocinolone acetonide is very minimal. bound to plasma proteins. No metabolism information is available for Acetazolamide. Fluocinolone acetonide metabolism: Following absorption, fluocinolone acetonide metabolism is primarily hepatic. It is important to mention that the systemically absorbed dose is very minimal. Acetazolamide is eliminated via No route of elimination available. Fluocinolone acetonide is eliminated via Fluocinolone acetonide is mainly excreted by the kidneys. It is important to mention that the systemically absorbed dose is very minimal. The half-life of Acetazolamide is 3 to 9 hours. The half-life of Fluocinolone acetonide is The reported half-life of fluocinolone acetonide ranges between 1. 3-1. 7 hours. No clearance information is available for Acetazolamide. The clearance of Fluocinolone acetonide is This pharmacokinetic parameter is not relevant as the systemic absorption of fluocinolone acetonide is very minimal and the concentration in urine is lower than the minimum quantitation limit. No toxicity information is available for Acetazolamide. Fluocinolone acetonide toxicity includes Studies to determine the carcinogenic and its effect in fertility have not been performed. It is important to consider that several corticosteroids have been shown to present genotoxic potential but fluocinolone acetonide was shown to not be genotoxic in the Ames test and mouse lymphoma TK assay. Brand names of Acetazolamide include No brand names available. Brand names of Fluocinolone acetonide include Capex, Derma-Smoothe/FS, Derma-smoothe FS, Dermotic, Flac, Iluvien, Neo-synalar, Otixal, Otovel, Retisert, Synalar, Tri-luma, Yutiq. No synonyms are available for Acetazolamide. Acetazolamida Acétazolamide Acetazolamide Acetazolamidum No synonyms are available for Fluocinolone acetonide. acetónido de fluocinolona fluocinolon acetonid Fluocinolone acetonide fluocinoloni acetonidum 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. Fluocinolone acetonide summary: It is Fluocinolone acetonide is a corticosteroid used to treat skin conditions, eczematous otitis externa, diabetic macular edema, and non-infectious uveitis of the posterior segment of the eye. 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 Obiltoxaximab. Drug B is Certolizumab pegol. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Obiltoxaximab is combined with Certolizumab pegol. Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions. Obiltoxaximab is indicated for Investigated for use/treatment in anthrax exposure, bacterial infection, crohn's disease, and graft versus host disease. 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. Obiltoxaximab pharmacodynamics: No pharmacodynamics available. 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. The mechanism of action of Obiltoxaximab is that it ETI-204 is an affinity-enhanced, de-immunized antibody, which means that its ability to bind to its target pathogen has been strengthened and that elements that might cause an immune response have been removed. ETI-204 targets and binds to Protective Antigen, which prevents the anthrax toxins from binding to and entering the cells in the body, thereby preventing death. The mechanism of action of 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. No absorption information is available for Obiltoxaximab. 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. No volume of distribution information is available for Obiltoxaximab. 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. No protein binding information is available for Obiltoxaximab. Certolizumab pegol is Monoclonal antibodies are usually not required to have protein binding studies. bound to plasma proteins. No metabolism information is available for Obiltoxaximab. 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. Obiltoxaximab is eliminated via No route of elimination available. 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. The half-life of Obiltoxaximab is No half-life available. The half-life of Certolizumab pegol is The circulatory half-life of certolizumab is of 14 days. No clearance information is available for Obiltoxaximab. 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. No toxicity information is available for Obiltoxaximab. 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. Brand names of Obiltoxaximab include Anthim. Brand names of Certolizumab pegol include Cimzia. No synonyms are available for Obiltoxaximab. No synonyms are available for Certolizumab pegol. Obiltoxaximab summary: It is Obiltoxaximab is a monoclonal antibody used for prophylaxis or treatment of inhalational anthrax. 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. Answer: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions. Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions.

Obiltoxaximab

Drug A is Bumetanide. Drug B is Cefoxitin. The severity of the interaction is moderate. The risk or severity of nephrotoxicity can be increased when Bumetanide is combined with Cefoxitin. Both the subject and the affected drug are known to cause some degree of nephrotoxicity. The concomitant use of multiple agents with this ability may result in an additive effect in which the incidence and/or severity of kidney damage is increased. Bumetanide is indicated for the treatment of edema associated with congestive heart failure, hepatic and renal disease including the nephrotic syndrome. Cefoxitin is indicated for the treatment of serious infections caused by susceptible strains microorganisms. Bumetanide pharmacodynamics: Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in patients in whom high doses of furosemide are ineffective. There is however no reason not to use bumetanide as a first choice drug. The main difference between the two substances is in bioavailability. Bumetanide has more predictable pharmacokinetic properties as well as clinical effect. In patients with normal renal function, bumetanide is 40 times more effective than furosemide. Cefoxitin pharmacodynamics: Cefoxitin is a cephamycin antibiotic often grouped with the second-generation cephalosporins. It is active against a broad range of gram-negative bacteria including anaerobes. The methoxy group in the 7a position provides cefoxitin with a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases, of gram-negative bacteria. The mechanism of action of Bumetanide is that it Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. The mechanism of action of Cefoxitin is that it The bactericidal action of cefoxitin results from inhibition of cell wall synthesis. Bumetanide absorption: Bumetanide is completely absorbed (80%), and the absorption is not altered when taken with food. Bioavailability is almost complete. No absorption information is available for Cefoxitin. No volume of distribution information is available for Bumetanide. No volume of distribution information is available for Cefoxitin. Bumetanide is 97% bound to plasma proteins. No protein binding information is available for Cefoxitin. Bumetanide metabolism: 45% is secreted unchanged. Urinary and biliary metabolites are formed by oxidation of the N-butyl side chain. Cefoxitin metabolism: Minimal (approximately 85 percent of cefoxitin is excreted unchanged by the kidneys over a 6-hour period). Bumetanide is eliminated via Oral administration of carbon-14 labeled Bumex to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Biliary excretion of Bumex amounted to only 2% of the administered dose. Cefoxitin is eliminated via Approximately 85 percent of cefoxitin is excreted unchanged by the kidneys over a 6-hour period, resulting in high urinary concentrations. Cefoxitin passes into pleural and joint fluids and is detectable in antibacterial concentrations in bile. The half-life of Bumetanide is 60-90 minutes. The half-life of Cefoxitin is The half-life after an intravenous dose is 41 to 59 minutes. The clearance of Bumetanide is 0. 2 - 1. 1 mL/min/kg [preterm and full-term neonates with respiratory disorders]. 2. 17 mL/min/kg [neonates receiving bumetanide for volume overload] 1. 8 +/- 0. 3 mL/min/kg [geriatric subjects] 2. 9 +/- 0. 2 mL/min/kg [younger subjects] No clearance information is available for Cefoxitin. Bumetanide toxicity includes Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels. Cefoxitin toxicity includes The acute intravenous LD50 in the adult female mouse and rabbit was about 8. 0 g/kg and greater than 1. 0 g/kg, respectively. The acute intraperitoneal LD50 in the adult rat was greater than 10. 0 g/kg. Brand names of Bumetanide include Bumex, Burinex. Brand names of Cefoxitin include No brand names available. No synonyms are available for Bumetanide. Bumetanide Bumetanidum No synonyms are available for Cefoxitin. Cefoxitina Cefoxitine Cefoxitinum Ceftoxitin Cephoxitin Rephoxitin Bumetanide summary: It is Bumetanide is a sulfamyl diuretic used to treat edema in congestive heart failure, hepatic and renal disease, and nephrotic syndrome. Cefoxitin summary: It is Cefoxitin is a semi-synthetic, broad-spectrum antibiotic for parenteral administration used for the treatment of serious bacterial infections, such as urinary tract infection, blood infection, bone and joint infection, and lower respiratory tract infection. Answer: Both the subject and the affected drug are known to cause some degree of nephrotoxicity. The concomitant use of multiple agents with this ability may result in an additive effect in which the incidence and/or severity of kidney damage is increased.

Bumetanide

Drug A is Coagulation Factor IX Human. Drug B is Dextran. The severity of the interaction is major. The therapeutic efficacy of Coagulation Factor IX Human can be decreased when used in combination with Dextran. Blood coagulation factors promote the blood coagulation pathways to ultimately form the insoluble fibrin clot. In contrast, fibrinolytic agents activate the fibrinolytic system by conversion of the inactive proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin to break down the insoluble clot [A38173]. Desired procoagulant effects of blood coagulation factors may be reduced with the combination use of fibrinolytic agents. Coagulation Factor IX Human is indicated for Factor IX is used to treat Christmas disease. Factor IX deficiency is treated by injection factor IX produced from human plasma. Tranexamic acid may be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding. Dextran is indicated for Dextran is used as the restoration of blood mass during surgical interventions if there is hypovolemia due to trauma or dehydration. It is as well used after the presence of hemorrhage in cases of blood loss to a level inferior to 15% of the blood mass, if compatibility test cannot be completed or when blood lots need to be tested for pathogen detection. Dextran is also used for the prevention of profound postoperative venous thrombosis. Dextran as well presents ophthalmic applications as solutions or ointments for the temporary relief of xerophthalmia or minor ocular irritations. Coagulation Factor IX Human pharmacodynamics: Binds vitamin K and factor VIIIa. Cleaves the Arg-Ile bond in factor X to form active factor Xa. Plays a key role in blood coagulation and clotting. Injections of factor IX are used to treat hemophilia B, which is sometimes called Christmas disease. AlphaNine is injected to increase plasma levels of Factor IX and can temporarily correct this coagulation defect. The activated partial thromboplastin time (aPTT) is prolonged in people with hemophilia B. Treatment with factor IX concentrate may normalize the aPTT by temporarily replacing the factor IX. The administration of BeneFIX increases plasma levels of factor IX, and can temporarily correct the coagulation defect in these patients. Dextran pharmacodynamics: It is reported that dextran presents an effect on the hemostatic system in particular by prolonging bleeding time. In the same trials, dextran is reported to reduce emboli, reduce platelet adhesiveness and produce hemodilution. These effects have been showed to be greater proportionally with the increase in the molecular weight of the dextran. The mechanism of action of Coagulation Factor IX Human is that it Coagulation Factor IX is an important protein in the process of hemostasis and normal blood clotting as it plays a key role within the coagulation cascade. It is located within the blood plasma as a zymogen, an antecedent to enzymatic function, in its inactivated state. Factor IX is dependent on the presence of Vitamin K, and is activated to a serine protease by the function of Coagulation Factor XIa. Factor XIa cleaves the peptide bond associated with protein activation in Factor IX, leaving Factor IX with two exposed chains, a light chain and a heavy chain. These two chains are held together by several disulfide bonds that reinforce the structure of Factor IX's activated form. After being activated, Factor IX forms a complex with calcium ions, membrane phospholipids and Coagulation Factor VIII to activate Coagulation Factor X. The activation of Factor X then performs a similarly integral step in the blood coagulation cascade. The ultimate result of phenotypically normal coagulation factors is the creation of platelets for normal blood clotting. The mechanism of action of Dextran is that it In preclinical studies, the mechanism of action is thought to be related to the blockage of the uptake of tissue plasminogen activator by mannose-binding receptors. This process has a direct effect by enhancing endogenous fibrinolysis. No absorption information is available for Coagulation Factor IX Human. Dextran absorption: Dextran presents a very low oral bioavailability that is reduced as the chain gets longer. Thus, the bioavailability of dextran is inversely proportional to the length of the carbohydrate chain. No volume of distribution information is available for Coagulation Factor IX Human. The volume of distribution of Dextran is The reported volume of distribution of dextran suggested a distribution throughout the blood volume. This volume of distribution is reported to be of around 120 ml. The organ that presented a higher accumulation of dextran was the liver. No protein binding information is available for Coagulation Factor IX Human. Dextran is Dextran is highly retained in the vascular system by binding to plasma proteins including albumin. bound to plasma proteins. No metabolism information is available for Coagulation Factor IX Human. Dextran metabolism: Long chains of dextran such as dextran 60 are highly metabolized in the liver until formation of lower molecular weight products before being excreted from the body. Coagulation Factor IX Human is eliminated via No route of elimination available. Dextran is eliminated via The elimination of dextran will depend on the length of the carbohydrate chain, the administration route, and the molecular weight. For dextran 1, it is reported to be mainly secreted unchanged in the urine in a ratio of 80% of the administered dose when administered parentally. It is registered that the weight threshold for unrestricted glomerular filtration is about 15 kDa and if the dextran overpasses 50 kDa it will not be renally eliminated in any significant amount. The half-life of Coagulation Factor IX Human is 18. 8 ± 5. 4 hours. The half-life of Dextran is The elimination half-life will depend on the length of the carbohydrate chain. The higher the molecular weight of the dextran the longer it will be the elimination half-life. The half-life will go from 1. 9 hours from dextran 1 to 42 hours in the case of dextran 60. The clearance of Coagulation Factor IX Human is 8. 62 ± 1. 7. No clearance information is available for Dextran. No toxicity information is available for Coagulation Factor IX Human. Dextran toxicity includes Some reports have shown adverse effects when used in therapeutical doses and some teratogenic effects have been demonstrated when used in large doses. The current LD50 reported in rats is 10700 mg/kg. Brand names of Coagulation Factor IX Human include Alphanine Sd, Balfaxar, Beriplex, Immunine Vh, Kcentra, Octaplex. Brand names of Dextran include Bion Tears, Colirio Ocusan, Genteal Tears, Genteal Tears Mild, Tears Naturale, Tears Renewed. No synonyms are available for Coagulation Factor IX Human. No synonyms are available for Dextran. Coagulation Factor IX Human summary: It is Coagulation Factor IX Human is a coagulation factor used to treat hemophilia B or factor IX hemophilia. Dextran summary: It is Dextran is a low molecular weight dextran used as an adjunctive treatment of shock or impending shock due to hemorrhage, burns, surgery or other trauma, as well as the prophylaxis of venous thrombosis and pulmonary embolism during high-risk medical 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.

Coagulation Factor IX Human

Drug A is Acetazolamide. Drug B is Clemastine. The severity of the interaction is moderate. The risk or severity of CNS depression can be increased when Clemastine is combined with Acetazolamide. Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually. Acetazolamide is indicated for adjunctive treatment of: edema due to congestive heart failure; drug-induced edema; centrencephalic epilepsies; chronic simple (open-angle) glaucoma. Clemastine is indicated for the relief of symptoms associated with allergic rhinitis such as sneezing, rhinorrhea, pruritus and acrimation. Also for the management of mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Used as self-medication for temporary relief of symptoms associated with the common cold. 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. Clemastine pharmacodynamics: Clemastine is an antihistamine that also induces anticholinergic and sedative effects. Antihistamines competitively antagonize various physiological effects of histamine including increased capillary permeability and dilatation, the formation of edema, the "flare" and "itch" response, and gastrointestinal and respiratory smooth muscle constriction. Within the vascular tree, H1- receptor antagonists inhibit both the vasoconstrictor and vasodilator effects of histamine. Depending on the dose, H1- receptor antagonists can produce CNS stimulation or depression. Most antihistamines exhibit central and/or peripheral anticholinergic activity. Antihistamines act by competitively blocking H1- receptor sites. Antihistamines do not pharmacologically antagonize or chemically inactivate histamine, nor do they prevent the release of histamine. 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 Clemastine is that it Clemastine is a selective histamine H1 antagonist and 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. No absorption information is available for Acetazolamide. Clemastine absorption: Rapidly absorbed from the gastrointestinal tract. No volume of distribution information is available for Acetazolamide. No volume of distribution information is available for Clemastine. Acetazolamide is 98% bound to plasma proteins. No protein binding information is available for Clemastine. No metabolism information is available for Acetazolamide. Clemastine metabolism: Antihistamines appear to be metabolized in the liver chiefly via mono- and didemethylation and glucuronide conjugation. Acetazolamide is eliminated via No route of elimination available. Clemastine is eliminated via Urinary excretion is the major mode of elimination. The half-life of Acetazolamide is 3 to 9 hours. The half-life of Clemastine is No half-life available. No clearance information is available for Acetazolamide. No clearance information is available for Clemastine. No toxicity information is available for Acetazolamide. Clemastine toxicity includes Oral LD 50 in rat and mouse is 3550 mg/kg and 730 mg/kg, respectively. Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. In children, stimulation predominates initially in a syndrome which may include excitement, hallucinations, ataxia, incoordination, muscle twitching, athetosis, hyperthermia, cyanosis convulsions, tremors, and hyperreflexia followed by postictal depression and cardio-respiratory arrest. Convulsions in children may be preceded by mild depression. Dry mouth, fixed dilated pupils, flushing of the face, and fever are common. In adults, CNS depression, ranging from drowsiness to coma, is more common. Brand names of Acetazolamide include No brand names available. Brand names of Clemastine include Wal-hist 12 Hr Relief. No synonyms are available for Acetazolamide. Acetazolamida Acétazolamide Acetazolamide Acetazolamidum No synonyms are available for Clemastine. Clemastine Clemastinum 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. Clemastine summary: It is Clemastine is an antihistamine with sedative and anticholinergic effects used to treat the symptoms of allergic rhinitis. Answer: Central nervous system (CNS) depressants can cause sedation, falls, respiratory depression, coma, and death. 2,3 The potential interaction between a CNS depressant and another CNS depressant drug due to synergistic effects is well documented in the literature, although the risk and severity of CNS depression vary from each drug. The subject and affected drugs are both CNS depressants that, when co-administered, may result in a more profound CNS depression. As the risk and severity of CNS depression resulting from the combined use of CNS depressants vary from each agent, each interaction between CNS depressants should be considered individually.

Acetazolamide

Drug A is Abemaciclib. Drug B is Dicloxacillin. The severity of the interaction is major. The metabolism of Abemaciclib can be increased when combined with Dicloxacillin. The subject drug is a CYP3A4 enzyme inducer of unknown strength, and the affected drug is metabolized by the CYP3A4 enzyme. Concomitant administration of these agents will induce the metabolism of the CYP3A4 substrate (affected drug), reducing the serum concentration and therapeutic effect. Drugs with a narrow therapeutic index must be maintained within a specific concentration range in order to be safe and efficacious. Reduced concentration of a drug with a narrow therapeutic index may lead to significantly lower efficacy. Abemaciclib is indicated for Indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. Inidicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Dicloxacillin is indicated for Used to treat infections caused by penicillinase-producing staphylococci which have demonstrated susceptibility to the drug. Abemaciclib pharmacodynamics: In combination with fulvestrant, the progression-free survival for patients with HR-positive, HER2-negative breast cancer was 16. 4 months compared to 9. 3 months for patients taking a placebo with fulvestrant. As a monotherapy, 19. 7% of patients taking abemaciclib achieved complete or partial shrinkage of their tumors for a median 8. 6 months after treatment. Abemaciclib induces cell cycle arrest and exerts an antitumor activity in human tumor xenograft models. In patient investigations and a healthy volunteer study, abemaciclib is not shown to induce any clinically significant changes in the QTc interval. Dicloxacillin pharmacodynamics: Dicloxacillin is a beta-lactamase resistant penicillin similar to oxacillin. Dicloxacillin has in vitro activity against gram-positive and gram-negative aerobic and anaerobic bacteria. The bactericidal activity of dicloxacillin results from the inhibition of cell wall synthesis and is mediated through dicloxacillin binding to penicillin binding proteins (PBPs). Dicloxacillin is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, and cephalosporinases and extended spectrum beta-lactamases. The mechanism of action of Abemaciclib is that it Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and tumor formation in various cancers. G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway. Activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins, which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb. Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point. This leads to increased expression of downstream signalling molecules and activity of protein kinases that promote the cell cycle progression and initiation of DNA replication. Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing. Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. Unlike other CDK inhibitors such as Palbociclib and Ribociclib, abemaciclib exhibits greater selectivity for CDK4 compared to CDK6. The mechanism of action of Dicloxacillin is that it Dicloxacillin exerts a bactericidal action against penicillin-susceptible microorganisms during the state of active multiplication. All penicillins inhibit the biosynthesis of the bacterial cell wall. By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, dicloxacillin inhibits the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins; it is possible that dicloxacillin interferes with an autolysin inhibitor. Abemaciclib absorption: The plasma concentration of the drug increases in a dose-proportional manner. Following a single oral dose administration of 200 mg abemaciclib, the mean peak plasma concentration (Cmax) of 158 ng/mL is reached after 6 hours. The median time to reach maximum plasma concentration (Tmax) ranges from 4-6 hours following an oral administration of abemaciclib over a range of 50–275 mg, but may range up to 24 hours. The absolute bioavailability of the drug is reported to be 45%. Dicloxacillin absorption: Absorption of the isoxazolyl penicillins after oral administration is rapid but incomplete: peak blood levels are achieved in 1-1. 5 hours. Oral absorption of cloxacillin, dicloxacillin, oxacillin and nafcillin is delayed when the drugs are administered after meals. The volume of distribution of Abemaciclib is The geometric mean systemic volume of distribution is approximately 690. 3 L (49% CV). No volume of distribution information is available for Dicloxacillin. Abemaciclib is According to in vitro models using animal brain tissues, the protein binding of abemaciclib is approximately 95-98%. While abemaciclib demonstrated in vitro binding to serum albumin, alpha-1-acid glycoprotein and other human plasma proteins in a concentration-depedent manner, its major metabolites are also shown to bind to plasms proteins as well. The approximate bound fractions of M2, M18 and M20 are 93. 4%, 96. 8% and 97. 8%, respectively. bound to plasma proteins. Dicloxacillin is Binds to serum protein, mainly albumin. bound to plasma proteins. Abemaciclib metabolism: Abemaciclib mainly undergoes hepatic metabolism mediated by CYP3A4. The major metabolite formed is N-desethylabemaciclib (M2), while other metabolites hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1) are also formed. M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively. No metabolism information is available for Dicloxacillin. Abemaciclib is eliminated via Following a single oral dose of 150mg radiolabeled abemaciclib, approximately 81% of the total dose was recovered in feces while 3% of the dose was detected in urine. The majority of the drug is exceted as metabolites. Dicloxacillin is eliminated via Dicloxacillin sodium is rapidly excreted as unchanged drug in the urine by glomerular filtration and active tubular secretion. The half-life of Abemaciclib is The mean plasma elimination half-life for abemaciclib in patients was 18. 3 hours (72% CV). The half-life of Dicloxacillin is The elimination half-life for dicloxacillin is about 0. 7 hour. The clearance of Abemaciclib is The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26. 0 L/h (51% CV). No clearance information is available for Dicloxacillin. Abemaciclib toxicity includes According to the bacterial reverse mutation (Ames) assay, abemaciclib and its active metbolites M2 and M20 did not display mutagenic properties. Abemaciclib was not clastogenic in vitro rat bone marrow micronucleus assay. Repeat-dose toxicity studies were performed to assess the effects of abemaciclib in testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0. 3 mg/kg/day in dogs which exceed the recommeded therapeutic doses in humans. The findings included decreased organ weights, intratubular cellular debris, hypospermia, tubular distillation, atrophy and degeneration or necrosis. Dicloxacillin toxicity includes Oral LD 50 in rat is 3579 mg/kg. Symptoms of overexposure include irritation, rash, labored breathing, hives, itching, wheezing, nausea, chills, and fever. Brand names of Abemaciclib include Verzenio. Brand names of Dicloxacillin include No brand names available. No synonyms are available for Abemaciclib. No synonyms are available for Dicloxacillin. Dicloxacillin Dicloxacillina Dicloxacilline Dicloxacillinum Abemaciclib summary: It is Abemaciclib is a medication used to treat HR+ HER2- advanced or metastatic breast cancer. Dicloxacillin summary: It is Dicloxacillin is a penicillin used to treat penicillinase-producing bacterial infections that are susceptible to the drug. Answer: The subject drug is a CYP3A4 enzyme inducer of unknown strength, and the affected drug is metabolized by the CYP3A4 enzyme. Concomitant administration of these agents will induce the metabolism of the CYP3A4 substrate (affected drug), reducing the serum concentration and therapeutic effect. Drugs with a narrow therapeutic index must be maintained within a specific concentration range in order to be safe and efficacious. Reduced concentration of a drug with a narrow therapeutic index may lead to significantly lower efficacy.

Abemaciclib

Drug A is Abciximab. Drug B is Golimumab. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Abciximab is combined with Golimumab. 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. Abciximab is indicated for Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting. Golimumab is indicated for Used in adults (i) as an adjunct to methotrexate treatment in patients with moderate to severe active rheumatoid arthritis (RA), (ii) in patients 2 years old and above with active psoriatic arthritis (PsA), (iii) as a single agent in patients with active ankylosing spondylitis (AS) or in combination with methotrexate, and (iv) as a single agent in patients with moderate to severe ulcerative colitis (UC) who require chronic steroids or have experienced intolerance or only a partial response to previous medications. It is also indicated (v) for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older. Abciximab pharmacodynamics: Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. A single intravenous bolus dose from 0. 15 mg/kg to 0. 30 mg/kg produced rapid dose-dependent inhibition of platelet function. After two hours post-injection with a dose of 0. 25 - 0. 30 mg/kg, 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation was prevented. GPIIb/IIIa is the major surface receptor involved in the final pathway of platelet aggregation. Bleeding time increases to over 30 minutes at the aforementioned doses. To compare, baseline values were five minutes. Golimumab pharmacodynamics: Golimumab inhibits the activity of the cytokine, tumor necrosis factor alpha (TNFα). In areas such as the joints and blood, increased TNFα is associated with chronic inflammation seen in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Thus golimumab decreases the inflammation in these conditions. Concerning ulcerative colitis, the physiological effects of golimumab has yet to be determined. The mechanism of action of Abciximab is that it Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. This binding is thought to involve steric hindrance and/or conformational alterations which block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. By binding to the vitronectin receptor (also known as the αvβ3 integrin), abciximab blocks effects mediated by this integrin which include cell adhesion. Furthermore, abciximab blocks Mac-1 receptor on monocytes and neutrophils thus inhibiting monocyte adhesion. The mechanism of action of Golimumab is that it As a human monoclonal antibody, golimumab binds and inhibits soluble and transmembrane human TNFα. Inhibition of TNFα prevents it binding to its receptors, which prevents both leukocyte infiltration through prevention of cell adhesion proteins such as E-selectin, ICAM-1 and VCAM-1, and pro-inflammatory cytokine secretion such as IL-6, IL-8, G-CSF and GM-CSF in vitro. Consequently, in patients with chronic inflammatory conditions, decreases in ICAM-1 and IL-6 as well as C-reactive protein (CRP), matrix metalloproteinase 3 (MMP-3), and vascular endothelial growth factor (VEGF) were observed. No absorption information is available for Abciximab. Golimumab absorption: After subcutaneous administration, golimumab can achieve maximum serum concentrations in 2 to 6 days and has an approximate bioavailability of 53%. In healthy volunteers, the maximum average concentration reached was 3. 2 ± 1. 4 μg/mL. No volume of distribution information is available for Abciximab. The volume of distribution of Golimumab is After IV administration, golimumab has a volume of distribution of about 58 to 126 mL/kg. This means that golimumab stays mostly in the circulatory system. No protein binding information is available for Abciximab. Golimumab is Plasma protein binding was not quantified. bound to plasma proteins. Abciximab metabolism: Most likely removed by opsonization via the reticuloendothelial system when bound to platelets, or by human antimurine antibody production. Excreted renally. Golimumab metabolism: The metabolism of golimumab has yet to be determined. Abciximab is eliminated via No route of elimination available. Golimumab is eliminated via The route of elimination for golimumab has yet to be determined. The half-life of Abciximab is Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. The half-life of Golimumab is Golimumab has a long half-life of about 2 weeks. No clearance information is available for Abciximab. The clearance of Golimumab is After one IV dose of golimumab, the systemic clearance was about 4. 9 to 6. 7 mL/day/kg. No toxicity information is available for Abciximab. Golimumab toxicity includes The FDA label includes a black box warning of serious infections and malignancy. Specifically there have been hospitalizations or death from infections such as bacterial sepsis, tuberculosis (TB), and invasive fungal (histoplasmosis) and other opportunistic infections. Additionally in children and adolescents taking golimumab, there have been lymphoma and other malignancies observed. Brand names of Abciximab include No brand names available. Brand names of Golimumab include Simponi. No synonyms are available for Abciximab. No synonyms are available for Golimumab. Abciximab summary: It is Abciximab is a monoclonal anti-glycoprotein IIb/IIIa receptor antibody used to prevent thrombosis during percutaneous coronary intervention. Golimumab summary: It is Golimumab is a TNFα inhibitor used in the symptomatic treatment of various active inflammatory disorders, such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. 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.

Abciximab

Drug A is Abrocitinib. Drug B is Sildenafil. The severity of the interaction is moderate. The serum concentration of Sildenafil can be increased when it is combined with Abrocitinib. 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. 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. 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. 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. 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 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 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. 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. 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 Abrocitinib is After intravenous administration, the volume of distribution of abrocitinib was approximately 100 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. 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. 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. 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. 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. 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. 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 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 Sildenafil is The terminal phase half-life observed for sildenafil is approximately 3 to 5 hours. The clearance of Abrocitinib is There is no information available. The clearance of Sildenafil is The total body clearance documented for sildenafil is 41 L/h. Abrocitinib toxicity includes There is no experience regarding human overdosage with abrocitinib. In clinical trials, there were no specific toxicities observed when abrocitinib was administered in single oral doses of 800 mg and 400 mg daily for 28 days. An overdose should be responded with symptomatic and supportive treatment, as there is no specific antidote for overdose with abrocitinib. 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 Abrocitinib include No brand names available. Brand names of Sildenafil include Liqrev, Revatio, Viagra, Vizarsin. No synonyms are available for Abrocitinib. No synonyms are available for Sildenafil. Sildenafilo Abrocitinib summary: It is Abrocitinib is a kinase inhibitor used to treat moderate-to-severe atopic dermatitis in adults. 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.

Abrocitinib

Drug A is Belantamab mafodotin. Drug B is Tibolone. The severity of the interaction is minor. Tibolone may increase the thrombogenic activities of Belantamab mafodotin. 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. 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. Tibolone is indicated for the relief of post-menopausal symptoms and for the prevention of osteoporosis. 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. Tibolone pharmacodynamics: Tibolone prevents bone loss and treating post-menopausal symptoms without stimulating the endometrial tissues, which may lead to malignancy. Typical, drugs that treat post-menopausal symptoms such as estrogen, have a proliferative effect on the endometrium, increasing the risk of endometrial carcinoma. The effects on the bone, brain and vaginal tissues can be explained by the estrogenic activity of tibolone. It is important to note that activity is not expressed in the endometrium. Tibolone behaves differently from estrogen plus progesterone combinations on the breast. Therefore, tibolone can be characterized as a selective estrogen activity regulator. Tibolone has been demonstrated to be an effective agent in treating symptoms associated with menopause. A 16 week trial in 1189 women examined the effect of tibolone 2. 5 mg once daily on climacteric symptoms. Women treated with tibolone showed improvement from baseline in typical menopausal symptoms including hot flashes, sweating, insomnia, and anxiety. 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 Tibolone is that it This drug's effects are owed to the activity of its metabolites in various tissues. Upon ingestion, tibolone is quickly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has progestogenic and androgenic effects. The specific tissue-selective effects of tibolone occur due to the metabolism, regulation of enzymes and receptor activation that varies in different tissues of the body. The bone-conserving effects occur due to estradiol receptor activation, while the progesterone and androgen receptors are not involved in this process. Breast tissue of monkeys is not found to be stimulated after tibolone administration, as occurs with estrogen plus progesterone used in combination. This is explained by the fact that tibolone and its metabolites inhibit sulphatase and 17 beta-hydroxysteroid dehydrogenase (HSD) type I and stimulate sulphotransferase and 17 beta-HSD type II. The combined effects of this process prevent the conversion to active estrogens. In the uterus, the progestogenic activity of the Delta(4)-metabolite and the effect on estrogen-inactivating enzymes prevent estrogenic stimulation. The mammary gland is not stimulated in currently used animal models. Tibolone has been shown to regulate estrogenic activity in several tissue types by influencing the availability of estrogenic compounds for the estradiol receptor in a selective manner. Additionally, tibolone modulates cellular homeostasis in the breast by preventing breast tissue proliferation and stimulating cell apoptosis. Tibolone does not stimulate the endometrium because of the action of its highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulfatase (inhibition)-sulfotransferase (stimulation) system. The estrogenic metabolites of tibolone have direct, favorable effects on the cardiovascular system and, in animal models, this drug has shown no adverse consequences. The tissue-selective effects of tibolone are the result of metabolism, enzyme regulation and receptor activation that vary in different tissues. The bone-preserving effects of tibolone are the result of estradiol receptor activation, while other steroid receptors, mainly the progesterone and androgen receptors, are not involved in this process. In a study of monkeys, breast tissue was not stimulated, which occurs with estrogen and progesterone, because tibolone and its metabolites inhibit sulfatase and 17 beta-hydroxysteroid _dehydrogenase (HSD) type I and stimulate _sulfotransferase and 17 beta-HSD type II. The simultaneous effects of this process halt conversion to active estrogens. Additionally, tibolone affects cellular homeostasis in the breast by preventing proliferation and stimulating apoptosis. Tibolone does not stimulate the endometrium due to the action of the highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulphatase (inhibition)-sulphotransferase (stimulation) pathway. The levels of tibolone metabolites and the alteration of hormonal activities vary according to the tissue type. In endometrial tissue the Δ4-isomer functions as a progestagen, however, in the brain and liver, it shows androgenic effects. In breast tissue, the primary actions of tibolone are strong inhibition of sulfatase activity and weak inhibition of 17β-hydroxysteroid dehydrogenase activity, which leads to blocking the conversion estrone sulfate to E2. 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. Tibolone absorption: Tibolone is extensively and rapidly absorbed after oral administration. The parent drug undergoes extensive metabolism, with. Greater than 80% of a radioactive dose excreted from the body as metabolites, which suggests very low plasma concentrations of tibolone. Plasma concentrations of the metabolites appear within 30 minutes and peak within 1–1. 5 hours. 2,7 The plasma concentrations of the hydroxymetabolites are higher than those of the ∆4-isomer. Food does not appear to have an effect on the absorption of this drug. The volume of distribution of Belantamab mafodotin is The mean steady state volume of distribution of belantamab mafodotin was 11 L. No volume of distribution information is available for Tibolone. Belantamab mafodotin is Monoclonal antibodies are generally not protein bound. bound to plasma proteins. Tibolone is Tibolone is 96% bound to plasma proteins, most likely albumin. 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. Tibolone metabolism: Tibolone is metabolized mainly in the liver. The cytochrome P450 isoenzyme system is involved in minor hydroxylation of tibolone. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has both progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulfated form. 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. Tibolone is eliminated via Excreted in the urine and feces in the form of sulfated metabolites. About 40% of the drug is excreted as metabolites in urine. The predominant route of elimination of tibolone is via the feces: about 60% of the drug is excreted as metabolites 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 Tibolone is The elimination half-life is approximately 45 h. 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 Tibolone is Elimination of tibolone is not dependent renal function. Belantamab mafodotin toxicity includes Data regarding overdose is not readily available. However, keratopathy was seen in 71% of patients. Tibolone toxicity includes >2000 mg/kg The Million Women Study (MWS), which had a prospective observational design, studied the use of hormone replacement therapy. The results indicated that the increase in the incidence of breast cancer with estrogen and progestogen (compared to estrogen alone) was greater than the reduction in occurrence of endometrial cancer associated with adding progestogen to estrogen therapy. The MWS also reported a marked increase in the incidence of breast cancer with tibolone and with implanted and transdermal estrogen-only preparations. Tibolone treatment in rodent studies showed an increased association with the development of a range of tumors in long-term oral carcinogenicity studies. These tumors included pituitary adenomas, mammary carcinomas and fibroadenomas, hepatic adenomas, uterine carcinoma, stromal polyps and stromal sarcoma, and carcinomas of the urinary bladder and testes. Tibolone failed to show any evidence of genotoxicity in studies for gene mutations, chromosomal damage as well as DNA damage. Other adverse effects these include dizziness, headache, nausea, abdominal pain, rashes, pruritus, weight gain, edema, and migraine. Brand names of Belantamab mafodotin include BLENREP. Brand names of Tibolone include No brand names available. No synonyms are available for Belantamab mafodotin. No synonyms are available for Tibolone. Tibolone tibolonum 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. Tibolone summary: It is No summary available. 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.

Belantamab mafodotin

Drug A is Bromazepam. Drug B is Deferasirox. The severity of the interaction is minor. The serum concentration of Bromazepam can be increased when it is combined with Deferasirox. Deferasirox is a CYP1A2 inhibitor, which may increase exposure to CYP1A2 substrates, especially those with a narrow therapeutic index. Bromazepam is indicated for the short-term treatment of insomnia, short-term treatment of anxiety or panic attacks, if a benzodiazepine is required, and the alleviation of the symptoms of alcohol- and opiate-withdrawal. Deferasirox is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. Bromazepam pharmacodynamics: Bromazepam is a lipophilic, long-acting benzodiazepine and with sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties. It does not possess any antidepressant qualities. Bromazepam, like other benzodiazepines, presents a risk of abuse, misuse, and dependence. According to many psychiatric experts, Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. Deferasirox pharmacodynamics: Deferasirox is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain. The mechanism of action of Bromazepam is that it Bromazepam binds to the GABA-A receptor producing a conformational change and potentiating its inhibitory effects. Other neurotransmitters are not influenced. The mechanism of action of Deferasirox is that it Two molecules of deferasirox are capable of binding to 1 atom of iron. Deferasirox works in treating iron toxicity by binding trivalent (ferric) iron (for which it has a strong affinity), forming a stable complex which is eliminated via the kidneys. Bromazepam absorption: Bioavailability is 84% following oral administration. The time to peak plasma level is 1 - 4 hours. Bromazepam is generally well absorbed after oral administration. Deferasirox absorption: The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The volume of distribution of Bromazepam is 1. 56 L/kg. The volume of distribution of Deferasirox is 14. 37 ± 2. 69 L. Bromazepam is 70% bound to plasma proteins. Deferasirox is Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. bound to plasma proteins. Bromazepam metabolism: Hepatically, via oxidative pathways (via an enzyme belonging to the Cytochrome P450 family of enzymes). One of the main metabolites is 3-hydroxybromazepam. It is pharmacologically active and the half life is similar to that of the parent compound. Deferasirox metabolism: Hepatic. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Bromazepam is eliminated via Urine (69%), as metabolites. Deferasirox is eliminated via Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The half-life of Bromazepam is 10-20 hours. The half-life of Deferasirox is The mean elimination half-life ranged from 8 to 16 hours following oral administration. The clearance of Bromazepam is 0. 82 mL/min/kg. No clearance information is available for Deferasirox. No toxicity information is available for Bromazepam. No toxicity information is available for Deferasirox. Brand names of Bromazepam include No brand names available. Brand names of Deferasirox include Exjade, Jadenu. No synonyms are available for Bromazepam. No synonyms are available for Deferasirox. Bromazepam summary: It is Bromazepam is a short-acting benzodiazepine with intermediate onset commonly used to treat panic disorders and severe anxiety. Deferasirox summary: It is Deferasirox is an iron chelator used to treat chronic iron overload caused by blood transfusions. Also used in patients with non-transfusion-dependent thalassemia syndromes, and in patients with elevated liver iron concentration and serum ferritin. Answer: Deferasirox is a CYP1A2 inhibitor, which may increase exposure to CYP1A2 substrates, especially those with a narrow therapeutic index.

Bromazepam

Drug A is Anakinra. Drug B is Ivosidenib. The severity of the interaction is major. The metabolism of Ivosidenib 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 CYP3A4 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. Ivosidenib is indicated for Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor approved for use in the US and Europe. It is indicated for the treatment of patients with a susceptible IDH1 mutation with: Newly Diagnosed Acute Myeloid Leukemia (AML) in combination azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults who have comorbidities that preclude the use of intensive induction chemotherapy. this indication is reserved for adults 75 years or older in the US. Relapsed or refractory AML in adults in the US. Locally Advanced or Metastatic Cholangiocarcinoma in adults who have been previously treated. Relapsed or Refractory Myelodysplastic Syndromes 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. Ivosidenib pharmacodynamics: Ivosidenib is an antineoplastic agent that is effective in cancers with a susceptible IDH1 mutation, which indicates increased levels of oncometabolite D-2-hydroxyglutarate (D-2HG) in cancer cells. Ivosidenib decreases D-2HG levels in a dose-dependent manner by inhibiting the IDH1 enzyme. Ivosidenib inhibits both the mutant and wild-type IDH1 but does not inhibit IDH2. 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 Ivosidenib is that it Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme in the cytoplasm and peroxisomes that plays a role in many cellular processes, including mitochondrial oxidative phosphorylation, glutamine metabolism, lipogenesis, glucose sensing, and regulation of cellular redox status. IDH1 converts isocitrate to α-ketoglutarate (α-KG), a normal metabolite in the carboxylic acid cycle. Multiple cancers are associated with missense mutations in IDH1, leading to the substitution of the amino acid arginine 132 in the enzyme active site, acquired gain-of-function activity, and increased enzyme activity. IDH1 mutation results in the accumulation of D-2-hydroxyglutarate (D-2HG), an oncometabolite that is structurally similar to α-KG. D-2HG inhibits α-KG-dependent dioxygenases, including histone and DNA demethylases, which play a role in histone and DNA demethylation along with other cellular processes. Inhibition of these enzymes leads to histone and DNA hypermethylation and a block in cell differentiation, including hematopoietic differentiation. With histone hypermethylation, methylation-sensitive insulators cannot regulate the activation of oncogenes. Excess D-2HG ultimately interferes with cellular metabolism and alters epigenetic regulation towards oncogenesis. Ivosidenib inhibits the mutant IDH1 at much lower concentrations than the wild-type enzyme. It targets gene mutations at position R132, with R132H and R132C being the most common mutations. In mouse xenograft models of IDH1-mutated AML, ivosidenib caused a decrease in D-2HG levels in a dose-dependent manner and induced myeloid differentiation in vitro and in vivo. Ivosidenib works to inhibit histone demethylases and restore normal methylation conditions to promote cell differentiation and oncogene regulation. 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. Ivosidenib absorption: Following oral administration, ivosidenib is rapidly absorbed. The Cmax following a single oral dose is 4503 ng/mL in patients with relapsed or refractory AML, 4820 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4060 ng/mL in patients with cholangiocarcinoma. The steady-state was reached within 14 days. The steady-state Cmax is 6551 ng/mL in patients with relapsed or refractory AML, 6145 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4799 ng/mL in patients with cholangiocarcinoma. The Tmax ranges from two to three hours. A high-fat meal increases ivosidenib exposure. 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 Ivosidenib is The apparent volume of distribution at steady state is 403 L in patients with relapsed or refractory AML, 504 L in patients with newly diagnosed AML who were also treated with azacitidine, and 706 L in patients with cholangiocarcinoma. No protein binding information is available for Anakinra. Ivosidenib is In vitro, ivosidenib is 92-96% bound to plasma proteins. bound to plasma proteins. Anakinra metabolism: As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body. Ivosidenib metabolism: Ivosidenib is predominantly metabolized by CYP3A4 via oxidation. The exact chemical structures of the metabolites formed from CYP3A4-mediated oxidation have not been fully characterized. Ivosidenib can also undergo N-dealkylation and hydrolysis as minor metabolic pathways. 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. Ivosidenib is eliminated via Following oral administration of ivosidenib, about 77% of the dose was eliminated in feces, where 67% was in the form of unchanged parent drug. About 17% of the dose was excreted in urine, where 10% was in the form of unchanged ivosidenib. 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 Ivosidenib is The terminal half-life at steady state is 58 hours in patients with relapsed or refractory AML, 98 hours in patients with newly diagnosed AML who were also treated with azacitidine, and 129 hours in patients with cholangiocarcinoma. 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 Ivosidenib is The apparent clearance at steady state is 5. 6 L/h in patients with relapsed or refractory AML, 4. 6 L/h in patients with newly diagnosed AML who were also treated with azacitidine, and 6. 1 L/h in patients with cholangiocarcinoma. 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. Ivosidenib toxicity includes There is limited information regarding the LD 50 or overdose of ivosidenib. Ivosidenib is associated with a risk of differentiation syndrome, Guillain-Barre syndrome, and embryo-fetal toxicity. Brand names of Anakinra include Kineret. Brand names of Ivosidenib include Tibsovo. No synonyms are available for Anakinra. No synonyms are available for Ivosidenib. 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). Ivosidenib summary: It is Ivosidenib is an isocitrate dehydrogenase-1 inhibitor used to treat acute myeloid leukemia and cholangiocarcinoma in adults with a susceptible IDH1 mutation. 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.

Anakinra

Drug A is Daratumumab. Drug B is Inotuzumab ozogamicin. The severity of the interaction is minor. The risk or severity of adverse effects can be increased when Inotuzumab ozogamicin is combined with Daratumumab. 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. Daratumumab is indicated for Daratumumab is indicated as an intravenous injection alone or in combination with other medications for the treatment of multiple myeloma. It is available as a combination product with hyaluronidase for the treatment of adults with multiple myeloma as monotherapy or combination therapy and light chain amyloidosis in combination with other drugs. Inotuzumab ozogamicin is indicated for Indicated as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B cell precursor acute lymphoblastic leukaemia (ALL). Daratumumab pharmacodynamics: Daratumumab is a monoclonal antibody that targets and induces apoptosis in cells that highly express CD38, including multiple myeloma cells. It has a long duration of action as it is given every 1-4 weeks. Patients should be counselled regarding the risk of hypersensitivity, neutropenia, thrombocytopenia, embryo-fetal toxicity, and interferences with cross-matching and red blood cell antibody screening. Inotuzumab ozogamicin pharmacodynamics: Inotuzumab ozogamicin is an antineoplastic agent that targets CD22 antigen expressed on immature B-cell lymphocytes and blocks further growth of tumor cells. The drug aims to restore normal blood counts and achieve complete remission from the disease. QT interval prolongation was observed in patients receiving inotuzumab ozogamicin. The mechanism of action of Daratumumab is that it CD38 is a glycoprotein present on the surface of hematopoietic cells and is responsible for a number of cell signalling functions. Daratumumab is an immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that targets CD38. Cancers like multiple myeloma overexpress CD38, allowing daratumumab to have higher affinity for these cells. This binding allows daratumumab to induce apoptosis, antibody dependent cellular phagocytosis, and antibody and complement-dependent cytotoxicity. Antibody dependent cellular phagocytosis is mediated by the FC region of the antibody inducing phagocytes such as macrophages, antibody dependent cellular cytotoxicity is mediated by the FC region of the antibody inducing effector cells such as natural killer cells, and complement dependent cytotoxicity is mediated by the FC region of the antibody binding to and inducing complement protein activity. The mechanism of action of Inotuzumab ozogamicin is that it Inotuzumab ozogamicin is comprised of cytotoxic antibiotic N-acetyl-gamma-calicheamicin dimethylhydrazide attached to a humanized monoclonal IgG4 antibody via 4-(4 acetylphenoxy) butanoic acid (acetyl butyrate) linker. The drug exerts a potent cytotoxic effect against CD22+ B-cell lymphoma when the antibody binds to the CD22 receptor on the surface of B cells. The drug-CD22 complex is rapidly internalized into the cell, forming an endosome which subsequently fuses with lysosomes. N-acetyl-gamma-calicheamicin dimethylhydrazide is then intracellularly released into the acidic environment. N-acetyl-gamma-calicheamicin dimethylhydrazide is a calicheamicin derivative, which is naturally produced by the bacterium Micromonospora echinospora, and is toxic to the body when not bound to the antibody. It mediates apoptosis of the cell by binding to the minor groove of DNA in a sequence-specific manner and undergoing a structural change to generate diradicals. These changes abstract hydrogen ions from the phosphodiester bonds of double-stranded DNA, resulting in breaks and cell apoptosis. Daratumumab absorption: Subcutaneous daratumumab reaches a Cmax of 592µg/mL compared to intravenous daratumumab, which reaches a Cmax of 688µg/mL. The AUC of subcutaneous daratumumab is 4017µg/mL*day compared to intravenous daratumumab, which has an AUC of 4019µg/mL*day. Inotuzumab ozogamicin absorption: Inotuzumab ozogamicin is intended to be administered in cycles that each run for 3 to 4 weeks. The steady state exposure of the drug is reached by Cycle 4. The mean (SD) maximum serum concentration (Cmax) of inotuzumab ozogamicin was 308 ng/mL (362) with patients receving the recommended dose of 1. 8 mg/m^2/cycle. The volume of distribution of Daratumumab is Daratumumab intravenous monotherapy has a volume of distribution of 4. 7 ± 1. 3L and the combination therapy has a volume of distribution of 4. 4 ± 1. 5L. Subcutaneous daratumumab has a volume of distribution of the central compartment of 5. 2L and a volume of distribution of the peripheral compartment of 3. 8L. The volume of distribution of Inotuzumab ozogamicin is The total volume of distribution of inotuzumab ozogamicin is approximately 12L. Daratumumab is Data regarding protein binding of daratumumab in serum is not readily available. bound to plasma proteins. Inotuzumab ozogamicin is In vitro studies show the binding of the N-acetyl-gamma-calicheamicin dimethylhydrazide to human plasma proteins to be approximately 97%. bound to plasma proteins. Daratumumab metabolism: Monoclonal antibodies are expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes. Inotuzumab ozogamicin metabolism: N-acetyl-gamma-calicheamicin dimethylhydrazide primarily undergoes nonenzymatic reduction in vitro. The metabolism of N-acetyl-gamma-calicheamicin dimethylhydrazide in human serum is not clearly understood as the level of the drug is below the limit of quantification of 50 pg/mL. The antibody portion of the drug is thought to undergo proteolytic degradation into amino acids then recycled into other proteins. Daratumumab is eliminated via Monoclonal antibodies are metabolized to amino acids used for synthesis of new proteins or are eliminated by the kidneys. Inotuzumab ozogamicin is eliminated via The drug is disposited in the body after administration. The half-life of Daratumumab is Intravenous daratumumab has a terminal half life of 18 ± 9 days. Subcutaneous daratumumab has a half life of 20 days. The half-life of Inotuzumab ozogamicin is The elimination half life at the end of Cycle 4 of administration is approximately 12. 3 days in a 2-compartment model. The clearance of Daratumumab is Intravenous daratumumab has a clearance of 171. 4 ± 95. 3mL/day. Subcutaneous daratumumab has a clearance of 119mL/day. The clearance of Inotuzumab ozogamicin is The clearance of inotuzumab ozogamicin at steady state is 0. 0333 L/h. Daratumumab toxicity includes Data regarding overdoses of daratumumab are not readily available. Patients should be treated with symptomatic and supportive measures. Inotuzumab ozogamicin toxicity includes Inotuzumab ozogamicin was shown to be clastogenic in vivo in the bone marrow of male mice but was not mutagenic in an* in vitro* bacterial reverse mutation (Ames) assay. In rat toxicity studies, rats developed oval cell hyperplasia, altered hepatocellular foci, and hepatocellular adenomas however the carcinogenic potential of inotuzumab ozogamicin on humans is undetermined. Based on reproductive toxicity studies involving female rats and non-clinical studies, inotuzumab ozogamicin has the potential to impair reproductive function and. fertility in men and women. Brand names of Daratumumab include Darzalex, Darzalex Faspro. Brand names of Inotuzumab ozogamicin include Besponsa. No synonyms are available for Daratumumab. No synonyms are available for Inotuzumab ozogamicin. Daratumumab summary: It is Daratumumab is a CD38-directed cytolytic antibody used alone or as an adjunct drug in the treatment of multiple myeloma and light chain amyloidosis. Inotuzumab ozogamicin summary: It is Inotuzumab ozogamicin is an antibody-drug conjugate used to treat B-cell precursor acute lymphoblastic leukemia (ALL). 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.

Daratumumab

Drug A is Budesonide. Drug B is Procaterol. The severity of the interaction is moderate. The risk or severity of hypokalemia can be increased when Budesonide is combined with Procaterol. This interaction is a theoretical interaction on the basis of possible hypokalemia. The combination of corticosteroids and long-acting adrenergic beta-2 agonists is a cornerstone of asthma therapy, however, based on the risk of hypokalemia from either agent, a possible drug interaction exists. Some corticosteroids are known to increase the risk of hypokalemia, especially at prolonged, elevated doses. Beta-2 adrenergic agonists can also cause hypokalemia through increased activation of the sodium-potassium pump, which leads to the shunting of potassium into cells. This effect of beta-2 adrenergic agonists is normally transient, not requiring potassium supplementation, but may become more severe with co-administration of corticosteroids or additional doses of the beta-2 agonist, especially when it is short-acting. The additive hypokalemic effects of these drugs may produce increased hypokalemia and potentiate the negative hypokalemia-related effects of beta-2 adrenergic agonists on cardiac rhythm. Beta-2 adrenergic agonists may cause ECG changes, including QT prolongation, tachycardia, and atrial fibrillation. 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. Procaterol is indicated for the treatment of asthma and chronic obstructive pulmonary disease (COPD). 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. Procaterol pharmacodynamics: Procaterol is a long-acting beta-2-adrenergic receptor agonist. It is a potent bronchodilator that may be administered orally or by aerosol inhalation. 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 Procaterol is that it Beta(2)-receptor stimulation in the lung causes relaxation of bronchial smooth muscle, bronchodilation, and increased bronchial airflow. 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. Procaterol absorption: Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended doses. 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 Procaterol. 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 Procaterol. 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. No metabolism information is available for Procaterol. 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. Procaterol 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 Procaterol is No half-life available. 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 Procaterol. 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. Procaterol toxicity includes Symptoms of overdose include angina (chest pain), dizziness, dry mouth, fatigue, flu-like symptoms, headache, heart irregularities, high or low blood pressure, high blood sugar, insomnia, muscle cramps, nausea, nervousness, rapid heartbeat, seizures, and tremor. Brand names of Budesonide include Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris. Brand names of Procaterol include No brand names available. No synonyms are available for Budesonide. Budesonide No synonyms are available for Procaterol. Budesonide summary: It is Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis. Procaterol summary: It is Procaterol is a beta-2 adrenergic receptor agonist and bronchodilator used for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Answer: This interaction is a theoretical interaction on the basis of possible hypokalemia. The combination of corticosteroids and long-acting adrenergic beta-2 agonists is a cornerstone of asthma therapy , however, based on the risk of hypokalemia from either agent, a possible drug interaction exists. Some corticosteroids are known to increase the risk of hypokalemia, especially at prolonged, elevated doses. Beta-2 adrenergic agonists can also cause hypokalemia through increased activation of the sodium-potassium pump, which leads to the shunting of potassium into cells. This effect of beta-2 adrenergic agonists is normally transient, not requiring potassium supplementation, but may become more severe with co-administration of corticosteroids or additional doses of the beta-2 agonist, especially when it is short-acting. The additive hypokalemic effects of these drugs may produce increased hypokalemia and potentiate the negative hypokalemia-related effects of beta-2 adrenergic agonists on cardiac rhythm. Beta-2 adrenergic agonists may cause ECG changes, including QT prolongation, tachycardia, and atrial fibrillation.

Budesonide

Drug A is Ropeginterferon alfa-2b. Drug B is Capsaicin. The severity of the interaction is moderate. The metabolism of Capsaicin can be decreased when combined with Ropeginterferon alfa-2b. Since both CYP1A2 substrates and inhibitors interact with the same enzyme, the concurrent administration of CYP1A2 inhibitors may decrease the metabolism of CYP1A2 substrates, increasing the latter exposure and their associated risk of toxicity. Ropeginterferon alfa-2b is indicated for Ropeginterferon alfa-2b is indicated for the treatment of adult patients with polycythemia vera. Capsaicin is indicated for The capsaicin 8% patch is indicated in the treatment of neuropathic pain associated with post-herpetic neuralgia. There are multiple topical capsaicin formulations available, including creams and solutions, indicated for temporary analgesia in muscle and join pain as well as neuropathic pain. 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. Capsaicin pharmacodynamics: Capsaicin is a TRPV1 receptor agonist. TRPV1 is a trans-membrane receptor-ion channel complex activated by temperatures higher than 43 degrees Celsius, pH lower than 6, and endogenous lipids. When activated by a combination of these factors, the channel can transiently open and initiate depolarization due to the influx of calcium and sodium ions. Because TRPV1 is commonly expressed in A-delta and mostly C fibers, depolarization results in action potentials which send impulses to the brain and spinal cord. These impulses result in capsaicin effects of warming, tingling, itching, stinging, or burning. Capsaicin also causes more persistent activation of these receptors compared to the environmental agonists, resulting in a loss of response to many sensory stimuli, described as "defunctionalization". Capsaicin is associated with many enzymatic, cytoskeletal, and osmotic changes, as well as disruption of mitochondrial respiration, impairing nociceptor function for extended periods of time. The mechanism of action of 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 Capsaicin is that it Capsaicin has been shown to reduce the amount of substance P associated with inflammation - however this is not believed to be its main mechanism in the relief of pain. Capsaicin's mechanism of action is attributed to "defunctionalization" of nociceptor fibers by inducing a topical hypersensitivity reaction on the skin. This alteration in pain mechanisms is due to many of the following: temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fiber terminals. 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. Capsaicin absorption: Oral: Following oral administration, capsaicin may be absorbed by a nonactive process from the stomach and whole intestine with an extent of absorption ranging between 50 and 90%, depending on the animal. The peak blood concentration can be reached within 1 hour following administration. Capsaicin may undergo minor metabolism in the small intestine epithelial cells post-absorption from the stomach into the small intestines. While oral pharmacokinetics information in humans is limited, ingestion of equipotent dose of 26. 6 mg of pure capsaicin, capsaicin was detected in the plasma after 10 minutes and the peak plasma concentration of 2. 47 ± 0. 13 ng/ml was reached at 47. 1 ± 2. 0 minutes. Systemic: Following intravenous or subcutaneous administration in animals, the concentrations in the brain and spinal cord were approximately 5-fold higher than that in blood and the concentration in the liver was approximately 3-fold higher than that in blood. Topical: Topical capsaicin in humans is rapidly and well absorbed through the skin, however systemic absorption following topical or transdermal administration is unlikely. For patients receiving the topical patch containing 179 mg of capsaicin, a population analysis was performed and plasma concentrations of capsaicin were fitted using a one-compartment model with first-order absorption and linear elimination. The mean peak plasma concentration was 1. 86 ng/mL but the maximum value observed in any patient was 17. 8 ng/mL. The volume of distribution of 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. No volume of distribution information is available for Capsaicin. No protein binding information is available for Ropeginterferon alfa-2b. No protein binding information is available for Capsaicin. Ropeginterferon alfa-2b metabolism: Ropeginterferon alfa-2b is expected to be catabolized by various proteolytic enzymes. Capsaicin metabolism: Capsaicin metabolism after oral administration is unclear, however it is expected to undergo metabolism in the liver with minimal metabolism in the gut lumen. In vitro studies with human hepatic microsomes and S9 fragments indicate that capsaicin is rapidly metabolized, producing three major metabolites, 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin, whereas vanillin was a minor metabolite. It is proposed that cytochrome P450 (P450) enzymes may play some role in hepatic drug metabolism. In vitro studies of capsaicin in human skin suggest slow biotransformation with most capsaicin remaining unchanged. Ropeginterferon alfa-2b is eliminated via Ropeginterferon alfa-2b is expected to be eliminated predominantly by hepatic metabolism. Capsaicin is eliminated via It is proposed that capsaicin mainly undergoes renal excretion, as both the unchanged and glucuronide form. A small fraction of unchanged compound is excreted in the feces and urine. In vivo animal studies demonstrates that less than 10 % of an administered dose was found in faces after 48 h. The half-life of 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 Capsaicin is Following oral ingestion of equipotent dose of 26. 6 mg of pure capsaicin, the half life was approximately 24. 9 ± 5. 0 min. Following topical application of 3% solution of capsaicin, the half-life of capsaicin was approximately 24 h. The mean population elimination half-life was 1. 64 h following application of a topical patch containing 179 mg of capsaicin. The clearance of 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. No clearance information is available for Capsaicin. 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. Capsaicin toxicity includes Acute oral LD50 and dermal LD50 in mouse are 47. 2 mg/kg and >512 mg/kg, respectively. Capsaicin is shown to be mutagenic for bacteria and yeast. Capsaicin can cause serious irritation, conjunctivitis and lacrimation via contact with eyes. It induces a burning sensation and pain in case of contact with eyes and skin. As it is also irritating to the respiratory system, it causes lung irritation and coughing as well as bronchoconstriction. Other respiratory effects include laryngospasm, swelling of the larynx and lungs, chemical pneumonitis,respiratory arrest and central nervous system effects such as convulsions and excitement. In case of ingestion, gastrointestinal tract irritation may be observed along with a sensation of warmth or painful burning. Symptoms of systemic toxicity include disorientation, fear, loss of body motor control including diminished hand-eye coordination, hyperventilation, tachycardia, and pulmonary oedema. Careful early decontamination is recommended and medical intervention should be initiated for any life-threatening symptoms. In case of contact, individual must be removed from the source of exposure and the contacted skin and mucous membranes should be thoroughly washed with copious amounts of water. Brand names of Ropeginterferon alfa-2b include Besremi. Brand names of Capsaicin include Capzasin Quick Relief, Capzasin-HP, Castiva Warming, Dendracin Neurodendraxcin, Lidopro, Medi-derm, Medi-derm With Lidocaine, Medrox, Qutenza, Rematex, Xoten-C, Zostrix. No synonyms are available for Ropeginterferon alfa-2b. No synonyms are available for Capsaicin. Capsaicina Isodecenoic acid vanillylamide Ropeginterferon alfa-2b summary: It is Ropeginterferon alfa-2b is a mono-pegylated type I interferon used to treat polycythemia vera. Capsaicin summary: It is Capsaicin is a topical analgesic agent used for the symptomatic relief of neuropathic pain associated with post-herpetic neuralgia, as well as other muscle and joint pain. Answer: Since both CYP1A2 substrates and inhibitors interact with the same enzyme, the concurrent administration of CYP1A2 inhibitors may decrease the metabolism of CYP1A2 substrates, increasing the latter exposure and their associated risk of toxicity.

Ropeginterferon alfa-2b

Drug A is Acenocoumarol. Drug B is Topiramate. The severity of the interaction is major. The metabolism of Acenocoumarol can be increased when combined with Topiramate. The subject drug is a weak CYP3A4 enzyme inducer, and the affected drug is metabolized by the CYP3A4 enzyme. Concomitant administration of these agents will induce the metabolism of the CYP3A4 substrate (affected drug), reducing the serum concentration and therapeutic effect. Drugs with a narrow therapeutic index must be maintained within a specific concentration range in order to be safe and efficacious. Reduced concentration of a drug with a narrow therapeutic index may lead to significantly lower efficacy. 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. Topiramate is indicated for Topiramate is indicated for the following conditions: 1)Monotherapy for partial onset or primary generalized tonic-clonic seizures for patients 2 years of age and above 2)Adjunctive therapy for partial onset seizures or primary generalized tonic-clonic seizures for both adult and pediatric patients above 2 years old 3)Adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in patients above 2 years of age 4)Prophylaxis of migraine in children 12 years of age and older and adults. Topiramate is also used off-label as an adjunct therapy for weight management and for mood disorders. 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. Topiramate pharmacodynamics: Topiramate prevents the occurrence of seizures and prevents migraine symptoms by reducing neural pathway excitability. It is important to note that this drug may cause metabolic acidosis, mood changes, suicidal thoughts and attempts, as well as kidney stones. When topiramate is combined with valproic acid, it is known to cause hypothermia. 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 Topiramate is that it A seizure is an abnormal and unregulated electrical discharge occurring in the brain. This leads to transient interruption in brain function, manifested by reduced alertness, abnormal sensations, and focal involuntary movements or convulsions. Several types of seizures exist, with common types including tonic-clonic seizures and partial onset seizures. The exact mechanisms by which topiramate exerts pharmacological actions on seizures and migraines are currently not fully characterized. Several properties of this drug, however, are likely to contribute to its therapeutic effects. Topiramate has been observed to exert actions on voltage-dependent sodium channels, GABA receptors, and glutamate receptors. Topiramate stimulates GABA-A receptor activity at brain non-benzodiazepine receptor sites and reduces glutamate activity at both AMPA and kainate receptors. Normally, GABA-A receptors are inhibitory and glutaminergic receptors are stimulatory for neuronal activity. By increasing GABA activity and inhibiting glutamate activity, topiramate blocks neuronal excitability, preventing seizures and migraines. Additionally, it blocks the voltage-dependent sodium channels, further blocking seizure activity. Topiramate has been shown to inhibit various carbonic anhydrase isozymes, but the clinical significance of this is unknown at this time. Acenocoumarol absorption: Rapidly absorbed orally with greater than 60% bioavailability. Peak plasma levels are attained 1 to 3 hours following oral administration. Topiramate absorption: After a 400mg dose in one clinical trial, topiramate reached maximal concentrations within 1. 8-4. 3 hours and ranged from 1. 73-28. 7 ug/mL. Food did not significantly affect the extent of absorption, despite delaying time to peak concentration. In patients with normal creatinine clearance, steady state concentrations are reached within 4 days. The bioavailability of topiramate in tablet form is about 80% compared to a topiramate solution. 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 Topiramate is The mean apparent volume of distribution of topiramate ranges from 0. 6-0. 8 L/kg when doses of 100mg to 1200mg are given. Topiramate readily crosses the blood-brain barrier. Acenocoumarol is 98. 7% protein bound, mainly to albumin bound to plasma proteins. Topiramate is Topiramate is not highly bound to plasma proteins, with an estimated plasma protein binding of 9-17% according to some studies. The FDA label indicates that the protein binding of topiramate is 15-41%. 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. Topiramate metabolism: The metabolites of topiramate are not known to be active. The metabolism of topiramate is characterized by reactions of glucuronidation, hydroxylation and hydrolysis that lead to the production of six minor metabolites. Some of topiramate's metabolites include 2,3-desisopropylidene topiramate, 4,5-desisopropylidene topiramate, 9-hydroxy topiramate, and 10-hydroxy topiramate. Acenocoumarol is eliminated via Mostly via the kidney as metabolites. Topiramate is eliminated via Topiramate is mainly eliminated through the kidneys. About 70-80% of the eliminated dose is found unchanged in the urine. The half-life of Acenocoumarol is 8 to 11 hours. The half-life of Topiramate is The elimination half-life is reported to be in the range of 19-23 hours. If topiramate is given with enzyme-inducers, the half-life can be reduced to 12-15 hours because of increased metabolism. No clearance information is available for Acenocoumarol. The clearance of Topiramate is The mean oral plasma clearance of topiramate ranges from 22-36 mL/min while the renal clearance is 17-18 mL/min, according to one pharmacokinetic study. The FDA label for topiramate indicates a similar oral plasma clearance of approximately 20 to 30 mL/min in adults. 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. Topiramate toxicity includes The LD50 of intraperitoneal topiramate in the rat is above 1500 mg/kg. Overdose information In a study of 4 healthy adult women taking topiramate, the severity of clinical effects following an overdose ranged from asymptomatic to severe, with no deaths reported. According to the FDA prescribing information for topiramate, an overdose may cause hypotension, severe metabolic acidosis, coma, abdominal pain, visual disturbances, convulsions, drowsiness, speech abnormalities, impaired mentation and coordination, stupor, agitation, dizziness, as well as depression. In the case of a recent ingestion of topiramate, the stomach contents should be emptied through the induction of emesis or gastric lavage. Offer supportive treatment, including activated charcoal and hemodialysis. Brand names of Acenocoumarol include No brand names available. Brand names of Topiramate include Eprontia, Qsymia, Qudexy, Topamax, Trokendi. No synonyms are available for Acenocoumarol. Acénocoumarol Acenocoumarol Acenocoumarolum Acenocumarol Acenocumarolo Acenokumarin Nicoumalone Nicumalon Nitrovarfarian Nitrowarfarin No synonyms are available for Topiramate. Tipiramato Topiramate Topiramato Topiramatum 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. Topiramate summary: It is Topiramate is an anticonvulsant drug used in the control of epilepsy and in the prophylaxis and treatment of migraines. Answer: The subject drug is a weak CYP3A4 enzyme inducer, and the affected drug is metabolized by the CYP3A4 enzyme. Concomitant administration of these agents will induce the metabolism of the CYP3A4 substrate (affected drug), reducing the serum concentration and therapeutic effect. Drugs with a narrow therapeutic index must be maintained within a specific concentration range in order to be safe and efficacious. Reduced concentration of a drug with a narrow therapeutic index may lead to significantly lower efficacy.

Acenocoumarol