The propensity for cytochrome P450 (CYP)3A4 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 work. Studies using human hepatocytes revealed moderate increases in CYP3A4 messenger RNA (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% - 86% and 47% - 72%, respectively, of rifampicin response across the three hepatocyte donor pools. In a clinical drug-drug interaction (DDI) study, mean midazolam Cmax and AUC 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 BID dose. The moderate impact on midazolam pharmacokinetics at the 500 mg BID 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 TID 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 Simcyp population-based simulator were in reasonable agreement with the observed clinical data. As the magnitude of the 4β-hydroxycholesterol or 6β-hydroxycortisol ratio change was generally smaller than the magnitude of midazolam AUC change with PF-06282999, a pharmacokinetic interaction study with midazolam ultimately proved important for assessment of drug-drug interaction via CYP3A4 induction.
- cytochrome P450
- drug development/discovery
- drug-drug interactions
- enzyme induction
- in vitro-in vivo prediction (IVIVE)
- physiologically-based pharmacokinetic modeling/PBPK
- The American Society for Pharmacology and Experimental Therapeutics