Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug-Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach.

Laura Maria Fuhr,Nina Hanke,Dominik Selzer,Thorsten Lehr,Fatima Zahra Marok

doi:10.3390/pharmaceutics13020270

Laura Maria Fuhr, Nina Hanke + Show 3 more

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https://doi.org/10.3390/pharmaceutics13020270

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Journal: Pharmaceutics	Publication Date: Feb 17, 2021
Citations: 34	License type: CC BY 4.0

Affiliation: Saarland University

Abstract

The anticonvulsant carbamazepine is frequently used in the long-term therapy of epilepsy and is a known substrate and inducer of cytochrome P450 (CYP) 3A4 and CYP2B6. Carbamazepine induces the metabolism of various drugs (including its own); on the other hand, its metabolism can be affected by various CYP inhibitors and inducers. The aim of this work was to develop a physiologically based pharmacokinetic (PBPK) parent−metabolite model of carbamazepine and its metabolite carbamazepine-10,11-epoxide, including carbamazepine autoinduction, to be applied for drug–drug interaction (DDI) prediction. The model was developed in PK-Sim, using a total of 92 plasma concentration−time profiles (dosing range 50–800 mg), as well as fractions excreted unchanged in urine measurements. The carbamazepine model applies metabolism by CYP3A4 and CYP2C8 to produce carbamazepine-10,11-epoxide, metabolism by CYP2B6 and UDP-glucuronosyltransferase (UGT) 2B7 and glomerular filtration. The carbamazepine-10,11-epoxide model applies metabolism by epoxide hydroxylase 1 (EPHX1) and glomerular filtration. Good DDI performance was demonstrated by the prediction of carbamazepine DDIs with alprazolam, bupropion, erythromycin, efavirenz and simvastatin, where 14/15 DDI AUClast ratios and 11/15 DDI Cmax ratios were within the prediction success limits proposed by Guest et al. The thoroughly evaluated model will be freely available in the Open Systems Pharmacology model repository.

Highlights

The anticonvulsant drug carbamazepine is known to induce multiple metabolizing enzymes
While carbamazepine is typically used as an inducer to investigate the interaction with a substrate, our study aims to provide a comprehensive overview on the pharmacokinetics of carbamazepine and its drug–drug interaction (DDI), investigating carbamazepine as inducer and as victim drug
58 and 34 plasma concentration−time profiles, and 4 and 5 fraction excreted unchanged in urine profiles, of carbamazepine and carbamazepine10,11-epoxide were used, respectively

Summary

Introduction

The anticonvulsant drug carbamazepine is known to induce multiple metabolizing enzymes. It is classified by the U.S Food and Drug Administration (FDA) as a strong inducer (area under the plasma concentration−time curve (AUC) decrease of victim drug. Carbamazepine itself is metabolized by the respective enzymes [2], with metabolism via CYP3A4 to the pharmacologically active metabolite carbamazepine-10,11-epoxide as one of the main routes of elimination [3]. Carbamazepine induces its own—as well as other drugs’—metabolism during multiple dose administration. Carbamazepine plasma levels can be affected by enzyme inhibitors and inducers. The coadministration of carbamazepine with other drugs, i.e., sensitive CYP3A4 or CYP2B6 substrates or perpetrators, can result in complex interaction patterns.

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