Pharmacokinetic Evaluation of CYP3A4-Mediated Drug-Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults

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• 作者：Robert Townsend ; Albert Dietz ; Christine Hale ; Shahzad Akhtar ; Donna Kowalski ; Christopher Lademacher ; Kenneth Lasseter ; Helene Pearlman ; Diane Rammelsberg ; Anne Schmitt-Hoffmann ; Takao Yamazaki and Amit Desai
• 刊名：Clinical Pharmacology in Drug Development
• 出版年：2017
• 出版时间：January/February 2017
• 年：2017
• 卷：6
• 期：1
• 页码：44-53
• 全文大小：285K
• ISSN：2160-7648

文摘

This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUC_τ) during a dosing interval by 90% and maximum concentration (C_max) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC_0-∞) and C_max by 422% and 9%, respectively. Isavuconazole was coadministered (200 mg 3 times daily for 2 days, then 200 mg once daily) with single doses of oral midazolam (3 mg; CYP3A4 substrate) or ethinyl estradiol/norethindrone (35 μg/1 mg; CYP3A4 substrate). Following coadministration, AUC_0-∞ increased 103% for midazolam, 8% for ethinyl estradiol, and 16% for norethindrone; C_max increased by 72%, 14%, and 6%, respectively. Most adverse events were mild to moderate in intensity; there were no deaths, and serious adverse events and adverse events leading to study discontinuation were rare. These results indicate that isavuconazole is a sensitive substrate and moderate inhibitor of CYP3A4.