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Research ArticleArticle

Pharmacokinetics and Disposition of the Thiouracil Derivative PF-06282999, an Orally Bioavailable, Irreversible Inactivator of Myeloperoxidase Enzyme, Across Animals and Humans

Jennifer Q. Dong, Manthena V. Varma, Angela Wolford, Tim Ryder, Li Di, Bo Feng, Steven G. Terra, Kazuko Sagawa and Amit S. Kalgutkar
Drug Metabolism and Disposition February 2016, 44 (2) 209-219; DOI: https://doi.org/10.1124/dmd.115.067868
Jennifer Q. Dong
Pfizer Inc., Cambridge, Massachusetts (J.Q.D., A.S.K.); and Pfizer Inc., Groton, Connecticut (M.V.V., A.W., T.R., L.D., B.F., S.G.T., K.S.)
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Manthena V. Varma
Pfizer Inc., Cambridge, Massachusetts (J.Q.D., A.S.K.); and Pfizer Inc., Groton, Connecticut (M.V.V., A.W., T.R., L.D., B.F., S.G.T., K.S.)
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Angela Wolford
Pfizer Inc., Cambridge, Massachusetts (J.Q.D., A.S.K.); and Pfizer Inc., Groton, Connecticut (M.V.V., A.W., T.R., L.D., B.F., S.G.T., K.S.)
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Tim Ryder
Pfizer Inc., Cambridge, Massachusetts (J.Q.D., A.S.K.); and Pfizer Inc., Groton, Connecticut (M.V.V., A.W., T.R., L.D., B.F., S.G.T., K.S.)
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Li Di
Pfizer Inc., Cambridge, Massachusetts (J.Q.D., A.S.K.); and Pfizer Inc., Groton, Connecticut (M.V.V., A.W., T.R., L.D., B.F., S.G.T., K.S.)
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Bo Feng
Pfizer Inc., Cambridge, Massachusetts (J.Q.D., A.S.K.); and Pfizer Inc., Groton, Connecticut (M.V.V., A.W., T.R., L.D., B.F., S.G.T., K.S.)
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Steven G. Terra
Pfizer Inc., Cambridge, Massachusetts (J.Q.D., A.S.K.); and Pfizer Inc., Groton, Connecticut (M.V.V., A.W., T.R., L.D., B.F., S.G.T., K.S.)
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Kazuko Sagawa
Pfizer Inc., Cambridge, Massachusetts (J.Q.D., A.S.K.); and Pfizer Inc., Groton, Connecticut (M.V.V., A.W., T.R., L.D., B.F., S.G.T., K.S.)
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Amit S. Kalgutkar
Pfizer Inc., Cambridge, Massachusetts (J.Q.D., A.S.K.); and Pfizer Inc., Groton, Connecticut (M.V.V., A.W., T.R., L.D., B.F., S.G.T., K.S.)
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Abstract

The thiouracil derivative PF-06282999 [2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide] is an irreversible inactivator of myeloperoxidase and is currently in clinical trials for the potential treatment of cardiovascular diseases. Concerns over idiosyncratic toxicity arising from bioactivation of the thiouracil motif to reactive species in the liver have been largely mitigated through the physicochemical (molecular weight, lipophilicity, and topological polar surface area) characteristics of PF-06282999, which generally favor elimination via nonmetabolic routes. To test this hypothesis, pharmacokinetics and disposition studies were initiated with PF-06282999 using animals and in vitro assays, with the ultimate goal of predicting human pharmacokinetics and elimination mechanisms. Consistent with its physicochemical properties, PF-06282999 was resistant to metabolic turnover from liver microsomes and hepatocytes from animals and humans and was devoid of cytochrome P450 inhibition. In vitro transport studies suggested moderate intestinal permeability and minimal transporter-mediated hepatobiliary disposition. PF-06282999 demonstrated moderate plasma protein binding across all of the species. Pharmacokinetics in preclinical species characterized by low to moderate plasma clearances, good oral bioavailability at 3- to 5-mg/kg doses, and renal clearance as the projected major clearance mechanism in humans. Human pharmacokinetic predictions using single-species scaling of dog and/or monkey pharmacokinetics were consistent with the parameters observed in the first-in-human study, conducted in healthy volunteers at a dose range of 20–200 mg PF-06282999. In summary, disposition characteristics of PF-06282999 were relatively similar across preclinical species and humans, with renal excretion of the unchanged parent emerging as the principal clearance mechanism in humans, which was anticipated based on its physicochemical properties and supported by preclinical studies.

Footnotes

    • Received October 14, 2015.
    • Accepted November 23, 2015.
  • This research was sponsored by Pfizer. At the time of data generation, all authors were employees and stockholders of Pfizer Inc. Pfizer Inc. provided support in the form of salaries for the authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • dx.doi.org/10.1124/dmd.115.067868.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (2)
Drug Metabolism and Disposition
Vol. 44, Issue 2
1 Feb 2016
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Research ArticleArticle

Disposition of PF-06282999 in Animals and Humans

Jennifer Q. Dong, Manthena V. Varma, Angela Wolford, Tim Ryder, Li Di, Bo Feng, Steven G. Terra, Kazuko Sagawa and Amit S. Kalgutkar
Drug Metabolism and Disposition February 1, 2016, 44 (2) 209-219; DOI: https://doi.org/10.1124/dmd.115.067868

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Research ArticleArticle

Disposition of PF-06282999 in Animals and Humans

Jennifer Q. Dong, Manthena V. Varma, Angela Wolford, Tim Ryder, Li Di, Bo Feng, Steven G. Terra, Kazuko Sagawa and Amit S. Kalgutkar
Drug Metabolism and Disposition February 1, 2016, 44 (2) 209-219; DOI: https://doi.org/10.1124/dmd.115.067868
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