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 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.

Development of a UPLC-MS/MS method for the determination of lacosamide and its metabolite and its application to drug-drug interaction

“…Many cardiovascular drugs are substrates for CYP3A4, CYP2C19, and CYP2C9, or inhibitors of these enzymes (Yuan et al, 2014;Zhou et al, 2014;Fuhr et al, 2022). In this study, after screening 7 potential cardiovascular drugs before the in vivo Frontiers in Pharmacology frontiersin.org study, 5 drugs with higher inhibitory rates were selected for their IC 50 values, all of which were less than 10 μM, and 2 drugs (felodipine, and nisoldipine) were selected for in vivo pharmacokinetic experiments in rats.…”

A physiologically‐based pharmacokinetic precision dosing approach to manage dasatinib drug–drug interactions

“…The developed PBPK model was applied to simulate dasatinib exposure in untested DDI scenarios with moderate and strong inhibitors as well as inducers of CYP3A4: The model was coupled with previously published PBPK perpetrator models of the inhibitors clarithromycin, 30 erythromycin, 36 fluconazole, 37 fluvoxamine, 38 grapefruit juice, 39 itraconazole, 30 and voriconazole 40 as well as the inducers carbamazepine 41 and efavirenz 41,42 to evaluate their impact on the exposure of dasatinib. Additionally, co‐administration of dasatinib with two perpetrator drugs simultaneously was investigated.…”

Characterization of Drug with Good Glass-Forming Ability Loaded Mesoporous Silica Nanoparticles and Its Impact Toward in vitro and in vivo Studies

“… [ 31 , 32 ] Felodipine 0.019 mg in 1 mL at 25°C Anti-hypertension Blocking calcium channels, mainly in vascular smooth muscles, causes a reduction in vascular resistance, which subsequently results in blood pressure lowering. [ 33 , 34 ] Fenofibrate 0.69 mg in 1 mL at 25°C Anti-hypertriglyceridemia Upregulate lipoprotein lipase, induce high-density lipoprotein (HDL) synthesis and decrease liver production of apolipoprotein C. Fibrates enhance the clearance of triglyceride-rich particles and plasma catabolism and fatty acid oxidation via acyl CoA synthetase and other enzymes. [ 35 , 36 ] Ibuprofen 21 mg in 1 L at 25°C Anti-inflammatory Inhibition of prostaglandin precursors.…”