title: 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.
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 300μM, 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 midazolamCmaxand 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-infandCmaxof ∼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.
authors.affiliation: 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.
authors.forename: Jennifer Q
authors.initials: JQ
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Gosset
authors.affiliation: 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.
authors.forename: Odette A
authors.initials: OA
authors.lastname: Fahmi
authors.affiliation: 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.
authors.forename: Zhiwu
authors.initials: Z
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Chabot
authors.affiliation: 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.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Terra
authors.affiliation: 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.
authors.forename: Vu
authors.initials: V
authors.lastname: Le
authors.affiliation: 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.
authors.forename: Kristin
authors.initials: K
authors.lastname: Chidsey
authors.affiliation: 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.
authors.forename: Parya
authors.initials: P
authors.lastname: Nouri
authors.affiliation: 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.
authors.forename: Albert
authors.initials: A
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Leonard
authors.initials: L
authors.lastname: Buckbinder
authors.affiliation: 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 amit.kalgutkar@pfizer.com.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009195:Peroxidase / Q000037:antagonists & inhibitors; D011744:Pyrimidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D055815:Young Adult
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D012333:RNA, Messenger; D009195:Peroxidase; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C000605149:2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide