1. Simultaneous Ivabradine Parent-Metabolite PBPK/PD Modelling Using a Bayesian Estimation Method
- Author
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Ludwig Vincent, Kayode Ogungbenro, Marylore Chenel, Jennifer Lang, and Aleksandra Galetin
- Subjects
Adult ,Male ,Physiologically based pharmacokinetic modelling ,Metabolite ,Cmax ,Pharmaceutical Science ,Administration, Oral ,Pharmacology ,030226 pharmacology & pharmacy ,Models, Biological ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Oral administration ,Heart Rate ,medicine ,Cytochrome P-450 CYP3A ,Humans ,Computer Simulation ,Drug Interactions ,Ivabradine ,Tissue Distribution ,Bayes Theorem ,Cardiovascular Agents ,Healthy Volunteers ,Fruit and Vegetable Juices ,Enterocytes ,Ketoconazole ,chemistry ,Intestinal Absorption ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Area Under Curve ,Cytochrome P-450 CYP3A Inhibitors ,Administration, Intravenous ,Female ,medicine.drug - Abstract
Ivabradine and its metabolite both demonstrate heart rate–reducing effect (If 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/AUCcontrol and Cmax+inhibitor/Cmaxcontrol 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).
- Published
- 2020