F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Non-Clinical Safety, Basel, Switzerland.
F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Non-Clinical Safety, Basel, Switzerland.
Eur J Pharm Sci. 2014 Jun 2;56:1-15. doi: 10.1016/j.ejps.2014.02.002. Epub 2014 Feb 12.
The induction of cytochrome P450 enzymes (CYPs) is an important source of drug-drug interaction (DDI) and can result in pronounced changes in pharmacokinetics (PK). Rifampicin (RIF) is a potent inducer of CYP3A4 and also acts as a competitive inhibitor which can partially mask the induction. The objective of this study was to determine a clinical DDI study design for RIF resulting in maximum CYP3A4 induction. A physiologically based pharmacokinetic (PBPK) model was developed to project the dynamics and magnitude of CYP3A4 induction in vivo from in vitro data generated with primary human hepatocytes. The interaction model included both inductive and inhibitory effects of RIF on CYP3A4 in gut and liver and accounting for the observed RIF auto-induction. The model has been verified for 4 CYP3A4 substrates: midazolam, triazolam, alfentanil and nifedipine using plasma concentration data from 20 clinical study designs with intravenous (n=7) and oral (n=13) administrations. Finally, the influence of the time between RIF and substrate administration was explored for the interaction between midazolam and RIF. The model integrating in vitro induction parameters correctly predicted intravenous induction but underestimated oral induction with 30% of simulated concentrations more than 2-fold higher than of observed data. The use of a 1.6-fold higher value for the maximum induction effect (Emax) improved significantly the accuracy and precision of oral induction with 82% of simulated concentrations and all predicted PK parameters within 2-fold of observed data. Our simulations suggested that a concomitant administration of RIF and midazolam resulted in significant competitive inhibition limited to intestinal enzyme. Accordingly, a maximum induction effect could be achieved with a RIF pretreatment of 600 mg/day during 5 days and a substrate administration at least 2 h after the last RIF dose. A period of 2 weeks after RIF removal was found sufficient to allow return to baseline levels of enzyme.
细胞色素 P450 酶（CYPs）的诱导是药物-药物相互作用（DDI）的重要来源，并可能导致药代动力学（PK）的显著变化。利福平（RIF）是 CYP3A4 的强效诱导剂，同时也是竞争性抑制剂，可部分掩盖诱导作用。本研究的目的是确定利福平导致最大 CYP3A4 诱导的临床 DDI 研究设计。开发了一种基于生理学的药代动力学（PBPK）模型，以从用原代人肝细胞产生的体外数据预测体内 CYP3A4 诱导的动力学和幅度。该相互作用模型包括 RIF 对肠道和肝脏中 CYP3A4 的诱导和抑制作用，并考虑了观察到的 RIF 自动诱导作用。该模型已使用 20 项静脉内（n=7）和口服（n=13）给药的临床研究设计的血浆浓度数据，对 4 种 CYP3A4 底物（咪达唑仑、三唑仑、阿芬太尼和硝苯地平）进行了验证。最后，探索了利福平和底物给药之间的时间间隔对咪达唑仑和利福平相互作用的影响。整合体外诱导参数的模型正确预测了静脉内诱导，但口服诱导的预测值低估了 30%的模拟浓度比观察数据高 2 倍以上。使用最大诱导效应（Emax）的 1.6 倍更高值可显著提高口服诱导的准确性和精密度，82%的模拟浓度和所有预测的 PK 参数都在观察数据的 2 倍以内。我们的模拟表明，利福平和咪达唑仑同时给药会导致仅限于肠道酶的显著竞争性抑制。因此，利福平预处理 600mg/天，持续 5 天，最后一次利福平剂量后至少 2 小时给予底物，可以实现最大诱导效应。在利福平去除后 2 周发现足以使酶恢复到基线水平。
