| Autor: |
Fuhr LM; Department of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany., Marok FZ; Department of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany., Mees M; Department of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany., Mahfoud F; Department of Internal Medicine III (Cardiology, Angiology, Intensive Care Medicine), Saarland University Medical Center and Saarland University Faculty of Medicine, 66421 Homburg, Germany.; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Selzer D; Department of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany., Lehr T; Department of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany. |
| Abstrakt: |
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 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. |
