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
| Autor: | James R. Gosset, Zhiwu Lin, Jeffrey R. Chabot, Odette A. Fahmi, Albert M. Kim, Vu Le, Parya Nouri, Amit S. Kalgutkar, Steven G. Terra, Leonard Buckbinder, Jennifer Q. Dong, Kristin Chidsey |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Population Cmax Pharmaceutical Science Pyrimidinones Pharmacology 030226 pharmacology & pharmacy Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Statistical significance Acetamides medicine Cytochrome P-450 CYP3A Humans heterocyclic compounds RNA Messenger Enzyme Inhibitors education Cells Cultured Peroxidase education.field_of_study CYP3A4 Cholesterol Area under the curve Middle Aged 030104 developmental biology chemistry Enzyme Induction Hepatocytes Midazolam Female medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 45:501-511 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.116.074476 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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