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

• Published in: Drug metabolism and disposition Vol. 45; no. 5; pp. 501 - 511
• Main Authors: Dong, Jennifer Q, Gosset, James R, Fahmi, Odette A, Lin, Zhiwu, Chabot, Jeffrey R, Terra, Steven G, Le, Vu, Chidsey, Kristin, Nouri, Parya, Kim, Albert, Buckbinder, Leonard, Kalgutkar, Amit S
• Format: Journal Article
• Language: English
• Published: United States 01-05-2017
• Subjects: Acetamides - pharmacokinetics; Acetamides - pharmacology; Adult; Cells, Cultured; Cytochrome P-450 CYP3A - biosynthesis; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Enzyme Induction - drug effects; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Female; Hepatocytes - drug effects; Hepatocytes - enzymology; Humans; Male; Middle Aged; Peroxidase - antagonists & inhibitors; Pyrimidinones - pharmacokinetics; Pyrimidinones - pharmacology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Young Adult
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.116.074476

The propensity for CYP3A4 induction by 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2
)-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
M, 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
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 AUC
and
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 4
-hydroxycholesterol/cholesterol and urinary 6
-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 4
-hydroxycholesterol or 6
-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.