Simultaneous Ivabradine Parent-Metabolite PBPK/PD Modelling Using a Bayesian Estimation Method

Ivabradine and its metabolite both demonstrate heart rate-reducing effect (I_f 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_+inhibitor/AUC_control and Cmax_+inhibitor/Cmax_control 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).