Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield S2 4SU, UK.
Curr Drug Metab. 2012 Jul;13(6):778-86. doi: 10.2174/138920012800840464.
Sex differences in the clearance of substrates of Cytochrome P4503A (CYP3A4) have been reported frequently although there has been no consensus on reasons for variation in observations amongst drugs which are seemingly all dependent on this enzyme for their metabolism. Moreover, these observations could not be replicated in all studies even when investigating the same drugs. Differing study designs and inadequate power to identify the sex differences may explain the conflicting reports. The aim of the current study was to use in vitro data on a number of CYP3A4 substrates to develop mechanistic population pharmacokinetic models which are capable of integrating various attributes of drugs and estimating the statistical power of in vivo studies designed to discern sex differences in the clearance of CYP3A4 substrates. Midazolam, triazolam, alprazolam, nifedipine and zolpidem were selected as test substrates. These compounds are predominantly metabolized by CYP3A4, unaffected by p-glycoprotein and have abundant clinical studies which can be used for validation purposes. Simulated apparent clearance, obtained by use of the Simcyp® Population-based Simulator and in vitro in vivo extrapolation (IVIVE) techniques, was compared in males and females after correcting for weight (CL/wt) in 1560 trials. Results suggested that about 105 subjects per study are required for an 80% probability of identifying a higher CL/wt in females with alprazolam, while the corresponding numbers for a similar power were 120, about 150 and 300 for nifedipine, triazolam and oral midazolam, respectively. The results were consistent with outcomes in published clinical studies and support the view that many of the published studies have inadequate power to detect these sex differences in drug clearance, thereby contributing to the lack of consensus on this subject.
尽管人们尚未就药物代谢中细胞色素 P4503A（CYP3A4）清除率的性别差异的原因达成共识，但经常有报道称其存在性别差异。而且，即使研究相同的药物，这些观察结果也不能在所有研究中得到复制。不同的研究设计和识别性别差异的能力不足可能解释了相互矛盾的报告。本研究的目的是利用 CYP3A4 多种底物的体外数据，开发能够整合药物各种特性并估计旨在识别 CYP3A4 底物清除率性别差异的体内研究统计功效的机制群体药代动力学模型。咪达唑仑、三唑仑、阿普唑仑、硝苯地平和唑吡坦被选为测试底物。这些化合物主要由 CYP3A4 代谢，不受 P-糖蛋白影响，并且有大量的临床研究可用于验证目的。在 1560 次试验中，使用 Simcyp®基于人群的模拟器和体外-体内外推（IVIVE）技术，校正体重后（CL/wt）比较了男性和女性的模拟表观清除率。结果表明，对于阿普唑仑，研究中每 105 例受试者中约有 1 例可能会识别出女性的 CL/wt 更高，而对于硝苯地平、三唑仑和口服咪达唑仑，具有相似功效的情况下，所需的受试者数量分别为 120、约 150 和 300。结果与已发表的临床研究结果一致，并支持这样一种观点，即许多已发表的研究在检测药物清除率中的这些性别差异方面的功效不足，从而导致在这个问题上缺乏共识。
