期刊
PHARMACEUTICS
卷 14, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics14071474
关键词
physiologically based pharmacokinetic (PBPK) modeling; pharmacodynamics; felodipine; drug-drug interactions (DDIs); cytochrome P450 3A4 (CYP3A4)
资金
- German Federal Ministry of Education and Research (BMBF) [031L0161C]
This study developed a PBPK/PD model of felodipine and its metabolite dehydrofelodipine for DDI predictions, successfully capturing their metabolic pathways and interactions with CYP3A4 perpetrators such as itraconazole, erythromycin, carbamazepine, and phenytoin.
The antihypertensive felodipine is a calcium channel blocker of the dihydropyridine type, and its pharmacodynamic effect directly correlates with its plasma concentration. As a sensitive substrate of cytochrome P450 (CYP) 3A4 with high first-pass metabolism, felodipine shows low oral bioavailability and is susceptible to drug-drug interactions (DDIs) with CYP3A4 perpetrators. This study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) parent-metabolite model of felodipine and its metabolite dehydrofelodipine for DDI predictions. The model was developed in PK-Sim (R) and MoBi (R) using 49 clinical studies (94 plasma concentration-time profiles in total) that investigated different doses (1-40 mg) of the intravenous and oral administration of felodipine. The final model describes the metabolism of felodipine to dehydrofelodipine by CYP3A4, sufficiently capturing the first-pass metabolism and the subsequent metabolism of dehydrofelodipine by CYP3A4. Diastolic blood pressure and heart rate PD models were included, using an E-max function to describe the felodipine concentration-effect relationship. The model was tested in DDI predictions with itraconazole, erythromycin, carbamazepine, and phenytoin as CYP3A4 perpetrators, with all predicted DDI AUC(last) and C-max ratios within two-fold of the observed values. The model will be freely available in the Open Systems Pharmacology model repository and can be applied in DDI predictions as a CYP3A4 victim drug.
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