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Research ArticleArticle

Examination of the Human Cytochrome P4503A4 Induction Potential of PF-06282999, an Irreversible Myeloperoxidase Inactivator: Integration of Preclinical, In Silico, and Biomarker Methodologies in the Prediction of the Clinical Outcome

Jennifer Q. Dong, James R. Gosset, Odette A. Fahmi, Zhiwu Lin, Jeffrey R. Chabot, Steven G. Terra, Vu Le, Kristin Chidsey, Parya Nouri, Albert Kim, Leonard Buckbinder and Amit S. Kalgutkar
Drug Metabolism and Disposition May 2017, 45 (5) 501-511; DOI: https://doi.org/10.1124/dmd.116.074476
Jennifer Q. Dong
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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James R. Gosset
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Odette A. Fahmi
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Zhiwu Lin
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Jeffrey R. Chabot
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Steven G. Terra
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Vu Le
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Kristin Chidsey
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Parya Nouri
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Albert Kim
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Leonard Buckbinder
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Amit S. Kalgutkar
Clinical Pharmacology (J.Q.D.), Pharmacokinetics, Pharmacodynamics, and Metabolism (J.R.G., J.R.C., A.S.K.), Statistics (V.L.), Early Clinical Development (K.C., A.K.), and Cardiovascular and Metabolic Disease Research Unit (L.B.), Pfizer Inc., Cambridge, Massachusetts; and Pharmacokinetics, Pharmacodynamics, and Metabolism (O.A.F., Z.L.), Clinical Development (S.G.T.), and Clinical Assay Group (P.N.), Pfizer Inc., Groton, Connecticut
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Abstract

The propensity for CYP3A4 induction by 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999), an irreversible inactivator of myeloperoxidase, was examined in the present study. Studies using human hepatocytes revealed moderate increases in CYP3A4 mRNA and midazolam-1′-hydroxylase activity in a PF-06282999 dose-dependent fashion. At the highest tested concentration of 300 μM, PF-06282999 caused maximal induction in CYP3A4 mRNA and enzyme activity ranging from 56% to 86% and 47% t0 72%, respectively, of rifampicin response across the three hepatocyte donor pools. In a clinical drug-drug interaction (DDI) study, the mean midazolam Cmax and area under the curve (AUC) values following 14-day treatment with PF-06282999 decreased in a dose-dependent fashion with a maximum decrease in midazolam AUC0–inf and Cmax of ∼57.2% and 41.1% observed at the 500 mg twice daily dose. The moderate impact on midazolam pharmacokinetics at the 500 mg twice daily dose of PF-06282999 was also reflected in statistically significant changes in plasma 4β-hydroxycholesterol/cholesterol and urinary 6β-hydroxycortisol/cortisol ratios. Changes in plasma and urinary CYP3A4 biomarkers did not reach statistical significance at the 125 mg three times daily dose of PF-06282999, despite a modest decrease in midazolam systemic exposure. Predicted DDI magnitude based on the in vitro induction parameters and simulated pharmacokinetics of perpetrator (PF-06282999) and victim (midazolam) using the Simcyp (Simcyp Ltd., Sheffield, United Kingdom) population-based simulator were in reasonable agreement with the observed clinical data. Since the magnitude of the 4β-hydroxycholesterol or 6β-hydroxycortisol ratio change was generally smaller than the magnitude of the midazolam AUC change with PF-06282999, a pharmacokinetic interaction study with midazolam ultimately proved important for assessment of DDI via CYP3A4 induction.

Footnotes

    • Received November 30, 2016.
    • Accepted February 28, 2017.
  • All authors are employees of, and/or held stock in Pfizer Inc. when this work was carried out.

  • https://doi.org/10.1124/dmd.116.074476.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 45 (5)
Drug Metabolism and Disposition
Vol. 45, Issue 5
1 May 2017
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Research ArticleArticle

CYP3A4 Induction Potential of PF-06282999

Jennifer Q. Dong, James R. Gosset, Odette A. Fahmi, Zhiwu Lin, Jeffrey R. Chabot, Steven G. Terra, Vu Le, Kristin Chidsey, Parya Nouri, Albert Kim, Leonard Buckbinder and Amit S. Kalgutkar
Drug Metabolism and Disposition May 1, 2017, 45 (5) 501-511; DOI: https://doi.org/10.1124/dmd.116.074476

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Research ArticleArticle

CYP3A4 Induction Potential of PF-06282999

Jennifer Q. Dong, James R. Gosset, Odette A. Fahmi, Zhiwu Lin, Jeffrey R. Chabot, Steven G. Terra, Vu Le, Kristin Chidsey, Parya Nouri, Albert Kim, Leonard Buckbinder and Amit S. Kalgutkar
Drug Metabolism and Disposition May 1, 2017, 45 (5) 501-511; DOI: https://doi.org/10.1124/dmd.116.074476
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