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The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Abrocitinib, a Selective Janus Kinase Inhibitor, in Humans. | LitMetric

The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Abrocitinib, a Selective Janus Kinase Inhibitor, in Humans.

Drug Metab Dispos

Medicine Design (M.E.D), Inflammation and Immunology (T.H.L., J.-B.T.), and Clinical Pharmacology (C.B.), Pfizer Inc., Cambridge, Massachusetts; Medicine Design (J.N.B., A.C.D., A.K.-A., R.S., G.S.W., J.L., T.C.G.) and Clinical Pharmacology (S.T.), Pfizer Inc., Groton, Connecticut; and Clinical Pharmacology, Pfizer Inc., New York, New York (B.K.M.)

Published: August 2022

AI Article Synopsis

  • Abrocitinib is an oral medication targeted for treating moderate-to-severe atopic dermatitis, with the study focusing on how it behaves in the body after being taken by male participants via oral and intravenous routes.
  • Key pharmacokinetic findings include a systemic clearance rate of 64.2 L/h, an absorption rate of over 90%, and a steady-state volume of distribution of 100 L, with the main drug remaining in the plasma being abrocitinib itself.
  • The study also notes the metabolic pathways, showing that abrocitinib is primarily eliminated via urine and metabolized mostly by cytochrome P450 enzymes, resulting in key metabolites (M1, M2, and M4) that exhibit varying

Article Abstract

Abrocitinib is an oral once-daily Janus kinase 1 selective inhibitor being developed for the treatment of moderate-to-severe atopic dermatitis. This study examined the disposition of abrocitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite (M) profiles. The results indicated abrocitinib had a systemic clearance of 64.2 L/h, a steady-state volume of distribution of 100 L, extent of absorption >90%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 60%. The half-life of both abrocitinib and total radioactivity was similar, with no indication of metabolite accumulation. Abrocitinib was the main circulating drug species in plasma (∼26%), with 3 major monohydroxylated metabolites (M1, M2, and M4) at >10%. Oxidative metabolism was the primary route of elimination for abrocitinib, with the greatest disposition of radioactivity shown in the urine (∼85%). In vitro phenotyping indicated abrocitinib cytochrome P450 fraction of metabolism assignments of 0.53 for CYP2C19, 0.30 for CYP2C9, 0.11 for CYP3A4, and ∼0.06 for CYP2B6. The principal systemic metabolites M1, M2, and M4 were primarily cleared renally. Abrocitinib, M1, and M2 showed pharmacology with similar Janus kinase 1 selectivity, whereas M4 was inactive. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of abrocitinib, a Janus kinase inhibitor for atopic dermatitis, in humans, as well as characterization of clearance pathways and pharmacokinetics of abrocitinib and its metabolites.

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Source
http://dx.doi.org/10.1124/dmd.122.000829DOI Listing

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