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Research ArticleArticle

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

Martin E. Dowty, Jinyan Lin, Tim F. Ryder, Weiwei Wang, Gregory S. Walker, Alfin Vaz, Gary L. Chan, Sriram Krishnaswami and Chandra Prakash
Drug Metabolism and Disposition April 2014, 42 (4) 759-773; DOI: https://doi.org/10.1124/dmd.113.054940
Martin E. Dowty
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts (M.E.D.); Pfizer Inc., Groton, Connecticut (J.L., T.F.R., W.W., G.S.W., A.V., C.P.); and Departments of Specialty Care Clinical Affairs (G.L.C.) and Clinical Pharmacology (S.K.), Pfizer Inc., Groton, Connecticut
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Jinyan Lin
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts (M.E.D.); Pfizer Inc., Groton, Connecticut (J.L., T.F.R., W.W., G.S.W., A.V., C.P.); and Departments of Specialty Care Clinical Affairs (G.L.C.) and Clinical Pharmacology (S.K.), Pfizer Inc., Groton, Connecticut
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Tim F. Ryder
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts (M.E.D.); Pfizer Inc., Groton, Connecticut (J.L., T.F.R., W.W., G.S.W., A.V., C.P.); and Departments of Specialty Care Clinical Affairs (G.L.C.) and Clinical Pharmacology (S.K.), Pfizer Inc., Groton, Connecticut
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Weiwei Wang
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts (M.E.D.); Pfizer Inc., Groton, Connecticut (J.L., T.F.R., W.W., G.S.W., A.V., C.P.); and Departments of Specialty Care Clinical Affairs (G.L.C.) and Clinical Pharmacology (S.K.), Pfizer Inc., Groton, Connecticut
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Gregory S. Walker
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts (M.E.D.); Pfizer Inc., Groton, Connecticut (J.L., T.F.R., W.W., G.S.W., A.V., C.P.); and Departments of Specialty Care Clinical Affairs (G.L.C.) and Clinical Pharmacology (S.K.), Pfizer Inc., Groton, Connecticut
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Alfin Vaz
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts (M.E.D.); Pfizer Inc., Groton, Connecticut (J.L., T.F.R., W.W., G.S.W., A.V., C.P.); and Departments of Specialty Care Clinical Affairs (G.L.C.) and Clinical Pharmacology (S.K.), Pfizer Inc., Groton, Connecticut
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Gary L. Chan
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts (M.E.D.); Pfizer Inc., Groton, Connecticut (J.L., T.F.R., W.W., G.S.W., A.V., C.P.); and Departments of Specialty Care Clinical Affairs (G.L.C.) and Clinical Pharmacology (S.K.), Pfizer Inc., Groton, Connecticut
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Sriram Krishnaswami
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts (M.E.D.); Pfizer Inc., Groton, Connecticut (J.L., T.F.R., W.W., G.S.W., A.V., C.P.); and Departments of Specialty Care Clinical Affairs (G.L.C.) and Clinical Pharmacology (S.K.), Pfizer Inc., Groton, Connecticut
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Chandra Prakash
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts (M.E.D.); Pfizer Inc., Groton, Connecticut (J.L., T.F.R., W.W., G.S.W., A.V., C.P.); and Departments of Specialty Care Clinical Affairs (G.L.C.) and Clinical Pharmacology (S.K.), Pfizer Inc., Groton, Connecticut
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Abstract

Tofacitinib is a novel, oral Janus kinase inhibitor. The objectives of this study were to summarize the pharmacokinetics and metabolism of tofacitinib in humans, including clearance mechanisms. Following administration of a single 50-mg 14C-labeled tofacitinib dose to healthy male subjects, the mean (standard deviation) total percentage of administered radioactive dose recovered was 93.9% (±3.6), with 80.1% (±3.6) in the urine (28.8% parent), and 13.8% (±1.9) in feces (0.9% parent). Tofacitinib was rapidly absorbed, with plasma concentrations and total radioactivity peaking at around 1 hour after oral administration. The mean terminal phase half-life was approximately 3.2 hours for both parent drug and total radioactivity. Most (69.4%) circulating radioactivity in plasma was parent drug, with all metabolites representing less than 10% each of total circulating radioactivity. Hepatic clearance made up around 70% of total clearance, while renal clearance made up the remaining 30%. The predominant metabolic pathways of tofacitinib included oxidation of the pyrrolopyrimidine and piperidine rings, oxidation of the piperidine ring side-chain, N-demethylation and glucuronidation. Cytochrome P450 (P450) profiling indicated that tofacitinib was mainly metabolized by CYP3A4, with a smaller contribution from CYP2C19. This pharmacokinetic characterization of tofacitinib has been consistent with its clinical experience in drug-drug interaction studies.

Footnotes

    • Received October 17, 2013.
    • Accepted January 24, 2014.
  • 1 Current affiliation: Amgen, Thousand Oaks, California.

  • 2 Current affiliation: Northeast Bioanalytical Laboratory, Hamden, Connecticut.

  • 3 Current affiliation: Biogenidec, Cambridge, Massachusetts.

  • This work was supported by Pfizer Inc.

  • dx.doi.org/10.1124/dmd.113.054940.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleArticle

Metabolism and Clearance of Tofacitinib in Humans

Martin E. Dowty, Jinyan Lin, Tim F. Ryder, Weiwei Wang, Gregory S. Walker, Alfin Vaz, Gary L. Chan, Sriram Krishnaswami and Chandra Prakash
Drug Metabolism and Disposition April 1, 2014, 42 (4) 759-773; DOI: https://doi.org/10.1124/dmd.113.054940

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Research ArticleArticle

Metabolism and Clearance of Tofacitinib in Humans

Martin E. Dowty, Jinyan Lin, Tim F. Ryder, Weiwei Wang, Gregory S. Walker, Alfin Vaz, Gary L. Chan, Sriram Krishnaswami and Chandra Prakash
Drug Metabolism and Disposition April 1, 2014, 42 (4) 759-773; DOI: https://doi.org/10.1124/dmd.113.054940
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