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® and MoBi® 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 Emax 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 AUClast and Cmax 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.
� Copyright©2013. Inventi Journals Pvt.Ltd. All Right Reserved.