Zhao Ping, Ragueneau-Majlessi Isabelle, Zhang Lei, Strong John M, Reynolds Kellie S, Levy Rene H, Thummel Kenneth E, Huang Shiew-Mei
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, USA.
J Clin Pharmacol. 2009 Mar;49(3):351-9. doi: 10.1177/0091270008331196.
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) approximately 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.
美国食品药品监督管理局的药物相互作用指南草案建议，为实现最大程度的CYP3A抑制作用，酮康唑（KTZ）应每日服用一次，每次400毫克，持续服用数天（QD400）。一些研究人员认为，鉴于其半衰期较短（t(1/2)约为3 - 5小时），单次服用400毫克（SD400）的KTZ就足够了。为确定KTZ给药方案对CYP3A抑制作用的影响，我们模拟了在存在SD400、QD400或每日两次、每次200毫克（BID200）KTZ的情况下，理论CYP3A底物的AUC变化倍数（AUCR）。AUCR的比值（AUCR(QD400)/AUCR(SD400)和AUCR(BID200)/AUCR(QD400)）随着生物利用度的增加和底物t(1/2)的增加而升高。SD400 KTZ给药方案可能仅对一部分底物（即低生物利用度和短t(1/2)的底物）提供最大抑制作用。对于t(1/2)长于KTZ的底物，多次服用KTZ至关重要，且BID200似乎比QD400能提供更大的抑制作用。此外，应优化KTZ的给药时间，以便在给予底物之前实现最大程度的首过酶抑制。
