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Quantitative Evaluation of Pharmacokinetic Inhibition of CYP3A Substrates by Ketoconazole: A Simulation Study

From the Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration (Dr Zhao, Dr Zhang, Dr Reynolds, Dr Huang); Department of Pharmaceutics, University of Washington, FDA sabbatical in 2007 and 2008 (Dr Ragueneau-Majlessi, Dr Levy, Dr Thummel); and Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration (Dr Strong).

The US Food and Drug Administration draft drug interaction guidance recommends that 400 mg ketoconazole (KTZ) be administered once daily for several days (QD400) for maximal CYP3A inhibition. Some investigators suggest that a single dose of 400 mg (SD400) KTZ is sufficient given its short half-life (t_1/2 3-5 hr). To determine the impact of KTZ regimens on CYP3A inhibition, we simulated AUC fold-change (AUCR) in the presence of SD400, QD400, or 200 mg twice-daily (BID200) KTZ for theoretical CYP3A substrates. Ratios of AUCR (AUCR_QD400/AUCR_SD400 and AUCR_BID200 AUCR_QD400) increase with increasing bioavailability and increasing substrate t_1/2. The SD400 KTZ regimen may provide maximal inhibition only for a subset of substrates (ie, low bioavailability and short t_1/2). For substrates with t_1/2 longer than that of KTZ, multiple KTZ dosing is critical and BID200 appears to provide greater inhibition than QD400. Also, timing of KTZ administration should be optimized to allow maximal presystemic enzyme inhibition prior to substrate administration.

Key Words: Ketoconazole • pharmacokinetics • CYP3A • inhibition • drug interaction • dosing regimen • bioavailability • half-life • FDA guidance

Address for reprints: Shiew-Mei Huang, PhD, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Room 3188, Building 51, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002; e-mail: shiewmei.huang{at}fda.hhs.gov.

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				S.-M. Huang and L. J. Lesko Authors' Response J. Clin. Pharmacol., March 1, 2009; 49(3): 370 - 370. [Full Text] [PDF]