Department of Pharmacology, Clinical Pharmacology, Cologne University Hospital, Gleueler Str. 24, 50931, Köln, Germany.
Clin Pharmacokinet. 2013 Sep;52(9):763-81. doi: 10.1007/s40262-013-0070-9.
Accurate predictions of cytochrome P450 (CYP) 3A-mediated drug-drug interactions (DDIs) account for dynamic changes of CYP3A activity at both major expression sites (liver and gut wall) by considering the full pharmacokinetic profile of the perpetrator and the substrate. Physiological-based in vitro-in vivo extrapolation models have become of increasing interest. However, due to discrepancies between the predicted and observed magnitude of DDIs, the role of models fully based on in vivo data is still essential.
The primary objective of this study was to develop a coupled dynamic model for the interaction of the CYP3A inhibitor voriconazole and the prototypical CYP3A substrate midazolam.
Raw concentration data were obtained from a DDI study. Ten subjects were given either no pretreatment (control) or voriconazole twice daily orally. Midazolam was given either intravenously or orally after the last voriconazole dose and during control phases. Data analysis was performed by the population pharmacokinetic approach using non-linear mixed effects modelling (NONMEM 7.2.0). Model evaluation was performed using visual predictive checks and bootstrap analysis.
A semiphysiological model was able to describe the pharmacokinetics of midazolam, its major metabolite and voriconazole simultaneously. By considering the temporal disposition of all three substances in the liver and gut wall, a time-varying CYP3A inhibition process was implemented. Only the incorporation of hypothetical enzyme site compartments resulted in an adequate fit, suggesting a sustained inhibitory effect through accumulation. Novel key features of this analysis are the identification of (1) an apparent sustained inhibitory effect by voriconazole due to a proposed quasi accumulation at the enzyme site, (2) a significantly reduced inhibitory potency of intravenous voriconazole for oral substrates, (3) voriconazole as a likely uridine diphosphate glucuronosyltransferase (UGT) 2B inhibitor and (4) considerable sources of interindividual variability.
The proposed semiphysiological modelling approach generated a mechanistic description of the complex DDI occurring at major CYP3A expression sites and thus may serve as a powerful tool to maximise information acquired from clinical DDI studies. The model has been shown to draw precise and accurate predictions. Therefore, simulations based on this kind of models may be used for various clinical scenarios to improve pharmacotherapy.
准确预测细胞色素 P450（CYP）3A 介导的药物-药物相互作用（DDI）需要考虑到诱导剂和底物的完整药代动力学特征，同时考虑到主要表达部位（肝脏和肠壁）中 CYP3A 活性的动态变化。基于生理学的体外-体内外推模型越来越受到关注。然而，由于预测和观察到的 DDI 程度之间存在差异，因此完全基于体内数据的模型仍然至关重要。
本研究的主要目的是建立一个用于 CYP3A 抑制剂伏立康唑和典型 CYP3A 底物咪达唑仑相互作用的耦合动态模型。
从 DDI 研究中获取原始浓度数据。10 名受试者分别给予伏立康唑或安慰剂（对照）每日两次口服。在最后一次伏立康唑给药后和对照期内，静脉内或口服给予咪达唑仑。数据通过非线性混合效应模型（NONMEM 7.2.0）进行群体药代动力学分析。使用可视化预测检查和自举分析进行模型评估。
半生理模型能够同时描述咪达唑仑、其主要代谢物和伏立康唑的药代动力学。通过考虑所有三种物质在肝脏和肠壁中的时间分布，实现了时间变化的 CYP3A 抑制过程。只有纳入假设的酶位室，才能得到适当的拟合，这表明通过积累存在持续的抑制作用。本分析的新特点包括：（1）由于在酶位上的拟似累积，伏立康唑产生明显的持续抑制作用；（2）静脉内伏立康唑对口服底物的抑制效力显著降低；（3）伏立康唑可能是尿苷二磷酸葡萄糖醛酸转移酶（UGT）2B 的抑制剂；（4）个体间变异性较大。
所提出的半生理建模方法对主要 CYP3A 表达部位发生的复杂 DDI 进行了机制描述，因此可能成为从临床 DDI 研究中获取最大信息量的有力工具。该模型已被证明能够做出精确和准确的预测。因此，基于这种模型的模拟可用于各种临床情况以改善药物治疗。
