A Physiologically Based Pharmacokinetic and Pharmacodynamic Model of the CYP3A4 Substrate Felodipine for Drug-Drug Interaction Modeling

Abstract

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.

Keywords: cytochrome P450 3A4 (CYP3A4); drug–drug interactions (DDIs); felodipine; pharmacodynamics; physiologically based pharmacokinetic (PBPK) modeling.

Figure 1

(a) Structure of a whole-body PBPK model. In this multi-compartmental modeling approach, compartments represent ADME-relevant organs of the body. The compartments are interconnected with arterial (red arrows) and venous (blue arrows) blood flows. (b) Metabolic pathways of felodipine and dehydrofelodipine and DDI network. Felodipine is metabolized by CYP3A4 to dehydrofelodipine, which is also metabolized by CYP3A4 (black arrows). Itraconazole and erythromycin are competitive (dotted red arrow) and mechanism-based (red arrow) inhibitors of CYP3A4, respectively, and inhibit the metabolism of felodipine and its metabolite, while carbamazepine and phenytoin induce CYP3A4. (c) Structure of the PBPK/PD model extension. Blood pressure and heart rate undergo diurnal variations (yellow). Alterations in diastolic blood pressure and heart rate are directly correlated to felodipine plasma concentrations (blue). Drawings by Servier, licensed under CC BY 3.0 [77]. CYP: cytochrome P450, DDI: drug–drug interaction, PBPK: physiologically based pharmacokinetic, PD: pharmacodynamics.

Figure 2

Predicted plasma concentration–time profiles of felodipine after administration as (a–c) intravenous infusion, (d) oral solution, (e–g) conventional tablet, or (h,i) extended-release tablet in comparison to observed data [11,35,45,47,48,51,71]. Observed data are shown as dots (felodipine) and triangles (dehydrofelodipine) ± standard deviation (if available); model predictions are shown as lines (blue: felodipine, green: dehydrofelodipine). bid: twice daily, HT: hypertensive, iv: intravenous, n: number of individuals, sd: single dose, sol: solution, tab: tablet, tabER: extended-release tablet.

Figure 3

Performance of the felodipine PBPK model. Predicted compared to observed AUC_last and C_max values of (a,b) felodipine and (c,d) dehydrofelodipine stratified by route of administration and health status of the study participants. The line of identity is shown as a solid line; 1.25-fold deviation is shown as dotted lines; 2-fold deviation is shown as dashed lines. Study references are listed in Table 1. AUC_last: area under the plasma concentration−time curve from the time of dosing to the time of last concentration measurement, C_max: maximum plasma concentration, iv: intravenous, sol: solution, tab: tablet, tabER: extended-release tablet, sd: single dose.

Figure 4

Predicted (a–c) plasma concentration–time profiles of felodipine with corresponding predicted (d–f) diastolic blood pressure (g–i) and heart rate effect–time profiles in healthy individuals (left panel) and hypertensive patients (center and right panels) in comparison to observed data [36,71,74]. Observed data are shown as dots and triangles ± standard deviation (if available); model predictions are shown as lines. HT: hypertensive, md: multiple dose, n: number of individuals, qd: once daily, sd: single dose, sol: solution, tab: tablet, tabER: extended-release tablet.

Figure 5

Upper row: predicted felodipine plasma concentration–time profiles with and without co-administration of the perpetrators (a) erythromycin, (b) itraconazole, and (c) carbamazepine and phenytoin in comparison to observed data [13,14,15]. Center row: predicted (d) diastolic blood pressure and (e) heart rate–time profiles with and without co-administration of itraconazole in comparison to observe data. Lower row: goodness-of-fit plots of predicted versus observed (f) DDI AUC_last ratios and (g) DDI C_max ratios. AUC_last: area under the plasma concentration−time curve from the time of dosing to the time of last concentration measurement, bid: twice daily, C_max: maximum plasma concentration, D: day, DDI: drug–drug interaction, n: number of individuals, sd: single dose, tab: tablet, tabER: extended-release tablet.