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

Jonathan N. Bauman, Angela C. Doran, Amanda King-Ahmad, Raman Sharma, Gregory S. Walker, Jian Lin, Tsung H Lin, Jean-Baptiste Telliez, Sakambari Tripathy, Theunis C. Goosen, Christopher Banfield, Bimal K Malhotra and Martin E Dowty
Drug Metabolism and Disposition June 14, 2022, DMD-AR-2022-000829; DOI: https://doi.org/10.1124/dmd.122.000829
Jonathan N. Bauman
1PDM, Pfizer Global R&D, United States
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Angela C. Doran
2Medicine Design - ADME Sciences, Pfizer, United States
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Amanda King-Ahmad
3Medicine Design, Pfizer Inc, United States
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Raman Sharma
4PDM Biotransformation, Pfizer, United States
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Gregory S. Walker
5PDM, Pfizer, United States
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Jian Lin
6PDM, Pfizer Inc, United States
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Tsung H Lin
7Inflammation and Immunology, Pfizer Inc, United States
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Jean-Baptiste Telliez
7Inflammation and Immunology, Pfizer Inc, United States
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Sakambari Tripathy
8Clinical Pharmacology, Pfizer Inc, United States
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Theunis C. Goosen
9Pharmacokinetics, Dynamics & Metabolism, Pfizer, Inc, United States
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Christopher Banfield
8Clinical Pharmacology, Pfizer Inc, United States
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Bimal K Malhotra
8Clinical Pharmacology, Pfizer Inc, United States
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Martin E Dowty
10Pfizer Inc, United States
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  • ORCID record for Martin E Dowty
  • For correspondence: martin.dowty@pfizer.com
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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 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 hour, and absolute oral bioavailability of 60%. The half-lifeof 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 mono-hydroxylated 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 JAK inhibitor for atopic dermatitis, in humans, as well as characterization of clearance pathways and pharmacokinetics of abrocitinib and its metabolites.

  • drug absorption
  • drug clearance
  • drug distribution
  • drug metabolism
  • excretion
  • human pharmacokinetics
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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Human ADME properties of abrocitinib

Jonathan N. Bauman, Angela C. Doran, Amanda King-Ahmad, Raman Sharma, Gregory S. Walker, Jian Lin, Tsung H Lin, Jean-Baptiste Telliez, Sakambari Tripathy, Theunis C. Goosen, Christopher Banfield, Bimal K Malhotra and Martin E Dowty
Drug Metabolism and Disposition June 14, 2022, DMD-AR-2022-000829; DOI: https://doi.org/10.1124/dmd.122.000829

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OtherArticle

Human ADME properties of abrocitinib

Jonathan N. Bauman, Angela C. Doran, Amanda King-Ahmad, Raman Sharma, Gregory S. Walker, Jian Lin, Tsung H Lin, Jean-Baptiste Telliez, Sakambari Tripathy, Theunis C. Goosen, Christopher Banfield, Bimal K Malhotra and Martin E Dowty
Drug Metabolism and Disposition June 14, 2022, DMD-AR-2022-000829; DOI: https://doi.org/10.1124/dmd.122.000829
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