Stoch S A, Friedman E, Maes A, Yee K, Xu Y, Larson P, Fitzgerald M, Chodakewitz J, Wagner J A
Merck & Co, Inc, Whitehouse Station, NJ, USA.
J Clin Pharmacol. 2009 Apr;49(4):398-406. doi: 10.1177/0091270008331133. Epub 2009 Feb 26.
Given the prominent role of cytochrome P450 3A (CYP3A) in the metabolism of drugs, it is critical to determine whether new chemical entities will be affected by the inhibition of this enzyme system and result in clinically relevant drug interactions. Ketoconazole interaction studies are frequently performed to determine a given compound's sensitivity to CYP3A metabolism. The present study evaluated whether probing a sensitive substrate (midazolam) with a potent inhibitor (ketoconazole) at earlier time points (days 1 or 2) might be used to reliably gauge the magnitude of a meaningful interaction. The geometric mean ratios (ketoconazole+midazolamday 5/ketoconazole+midazolamday 1 and ketoconazole+midazolamday 5/ketoconazole+midazolamday 2) for midazolam AUC0-infinity were 1.36 and 1.06 with corresponding 90% confidence intervals of (1.17, 1.57) and (0.83, 1.23), respectively. These findings suggest that short-term drug-drug interaction studies can predict the magnitude of change in AUC as reliably as studies using longer duration treatments.
鉴于细胞色素P450 3A（CYP3A）在药物代谢中发挥的重要作用，确定新的化学实体是否会受到该酶系统抑制的影响并导致具有临床意义的药物相互作用至关重要。酮康唑相互作用研究经常用于确定给定化合物对CYP3A代谢的敏感性。本研究评估了在更早的时间点（第1天或第2天）用强效抑制剂（酮康唑）探测敏感底物（咪达唑仑）是否可用于可靠地评估有意义相互作用的程度。咪达唑仑AUC0-∞的几何平均比值（酮康唑+咪达唑仑第5天/酮康唑+咪达唑仑第1天和酮康唑+咪达唑仑第5天/酮康唑+咪达唑仑第2天）分别为1.36和1.06，相应的90%置信区间分别为（1.17, 1.57）和（0.83, 1.23）。这些发现表明，短期药物-药物相互作用研究能够像使用更长疗程治疗的研究一样可靠地预测AUC的变化幅度。
