Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
Centre de Pharmacocinétique et Métabolisme, Technologie Servier, Orléans, France.
AAPS J. 2020 Oct 8;22(6):129. doi: 10.1208/s12248-020-00502-8.
Ivabradine and its metabolite both demonstrate heart rate-reducing effect (I current inhibitors) and undergo CYP3A4 metabolism. The purpose of this study was to develop a joint parent-metabolite physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model to predict the PK and PD of ivabradine and its metabolite following intravenous (i.v.) or oral administration (alone or co-administered with CYP3A4 inhibitors). Firstly, a parent-metabolite disposition model was developed and optimised using individual plasma concentration-time data following i.v. administration of ivabradine or metabolite within a Bayesian framework. Secondly, the model was extended and combined with a mechanistic intestinal model to account for oral absorption and drug-drug interactions (DDIs) with CYP3A4 inhibitors (ketoconazole, grapefruit juice). Lastly, a PD model was linked to the PBPK model to relate parent and metabolite PK to heart rate (HR) reduction. The disposition model described successfully parent-metabolite PK following i.v. administration. Following integration of a gut model, the PBPK model adequately predicted plasma concentration profiles and the DDI risk (92% and 85% of predicted AUC/AUC and Cmax/Cmax for ivabradine and metabolite within the prediction limits). Ivabradine-metabolite PBPK model was linked to PD by using the simulated unbound parent-metabolite concentrations in the heart. This approach successfully predicted the effects of both entities on HR (observed vs predicted - 7.7/- 5.9 bpm and - 15.8/- 14.0 bpm, control and ketoconazole group, respectively). This study provides a framework for PBPK/PD modelling of a parent-metabolite and can be scaled to other populations or used for investigation of untested scenarios (e.g. evaluation of DDI risk in special populations).
依伐布雷定及其代谢产物均具有降低心率的作用（I 类钙通道抑制剂），并通过 CYP3A4 代谢。本研究旨在建立一个联合的母体-代谢物生理基于药代动力学（PBPK）/药效动力学（PD）模型，以预测依伐布雷定及其代谢产物静脉（i.v.）或口服（单独或与 CYP3A4 抑制剂共同给药）后的 PK 和 PD。首先，在贝叶斯框架内，使用个体静脉内给予依伐布雷定或代谢物后的血浆浓度-时间数据，开发和优化了一个母体-代谢物处置模型。其次，该模型通过与一个机械肠道模型相结合进行扩展，以解释口服吸收和与 CYP3A4 抑制剂（酮康唑、葡萄柚汁）的药物相互作用（DDI）。最后，将 PD 模型与 PBPK 模型相联系，将母体和代谢物 PK 与心率（HR）降低相关联。该处置模型成功描述了静脉内给药后母体-代谢物 PK。在整合肠道模型后，PBPK 模型能够充分预测血浆浓度曲线和 DDI 风险（依伐布雷定和代谢物的 AUC/AUC 和 Cmax/Cmax 预测值在预测范围内的 92%和 85%）。通过使用心脏中模拟的未结合母体-代谢物浓度，将依伐布雷定-代谢物 PBPK 模型与 PD 相联系。该方法成功预测了两种药物对 HR 的影响（观察值与预测值分别为-7.7/-5.9 bpm 和-15.8/-14.0 bpm，对照组和酮康唑组）。本研究为母体-代谢物的 PBPK/PD 建模提供了一个框架，可以扩展到其他人群或用于研究未经测试的情况（例如，评估特殊人群中的 DDI 风险）。
