Department of Pharmacokinetics and Drug Metabolism, 30E-2-C, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
Drug Metab Dispos. 2011 Jul;39(7):1139-48. doi: 10.1124/dmd.111.038067. Epub 2011 Mar 25.
Rifampin and carbamazepine have been recommended in the U.S. Food and Drug Administration draft drug interaction guidance as CYP3A4 inducers for clinical drug-drug interaction (DDI) studies. To optimize the dose regimens of these inducers for use in DDI studies, their effect at various doses and dosing durations on the area under the curve (AUC) of multiple probe substrates was simulated using a population-based simulator. A similar assessment of the inducer phenobarbital was also conducted. CYP3A4 induction by all three inducers was previously determined in hepatocytes, and the results were incorporated into simulations. The pharmacokinetics of the three inducers and their associated CYP3A4 drug interactions were predicted and compared with in vivo observations. The predicted C(max) and AUC of all the inducers and substrates correlated closely with those observed clinically. The predicted magnitudes of the DDIs caused by CYP3A4 induction were also in good agreement with the observed clinical results. Comparison of the maximal CYP3A4 induction potential among the three inducers indicated that rifampin is the most potent inducer and is the best choice for clinical CYP3A4 induction DDI studies. Moreover, a near-maximal CYP3A4 DDI was predicted to result from administration of rifampin for approximately 7 days at 450 to 600 mg q.d. or 200 to 300 mg b.i.d. These results suggest optimal dose regimens for clinical trials that maximize the probability of detecting a DDI caused by CYP3A4 induction. The simulation strategy provides the means to predict the induction profiles of compounds in development.
利福平与卡马西平被美国食品药品监督管理局（FDA）的药物相互作用指导草案推荐为 CYP3A4 诱导剂，用于临床药物相互作用（DDI）研究。为优化这些诱导剂在 DDI 研究中的剂量方案，使用基于人群的模拟器模拟了不同剂量和给药持续时间对多个探针底物的曲线下面积（AUC）的影响。同时也对诱导剂苯巴比妥进行了类似的评估。先前已经在肝细胞中确定了这三种诱导剂对 CYP3A4 的诱导作用，并且将结果纳入了模拟中。预测了三种诱导剂及其相关 CYP3A4 药物相互作用的药代动力学，并将预测结果与体内观察结果进行了比较。所有诱导剂和底物的预测 C(max)和 AUC 与临床观察结果密切相关。CYP3A4 诱导引起的 DDI 的预测幅度也与观察到的临床结果非常吻合。三种诱导剂之间最大 CYP3A4 诱导潜力的比较表明，利福平是最强的诱导剂，是用于临床 CYP3A4 诱导 DDI 研究的最佳选择。此外，预计给予利福平约 7 天，每天 450 至 600 毫克或每天两次 200 至 300 毫克，将导致近最大 CYP3A4 DDI。这些结果表明了临床试验的最佳剂量方案，可最大限度地提高检测 CYP3A4 诱导引起的 DDI 的可能性。模拟策略提供了预测开发中化合物诱导特征的手段。
