Please use this identifier to cite or link to this item: doi:10.22028/D291-33452
Title: Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug–Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach
Author(s): Fuhr, Laura Maria
Marok, Fatima Zahra
Hanke, Nina
Selzer, Dominik
Lehr, Thorsten
Language: English
Title: Pharmaceutics
Volume: 13
Issue: 2
Publisher/Platform: MDPI
Year of Publication: 2021
Free key words: physiologically based pharmacokinetic (PBPK) modeling
drug–drug interactions (DDIs)
cytochrome P450 3A4 (CYP3A4)
cytochrome P450 2B6 (CYP2B6)
DDC notations: 500 Science
Publikation type: Journal Article
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.
DOI of the first publication: 10.3390/pharmaceutics13020270
Link to this record: urn:nbn:de:bsz:291--ds-334520
ISSN: 1999-4923
Date of registration: 1-Mar-2021
Description of the related object: Supplementary Materials
Related object:
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Pharmazie
Professorship: NT - Prof. Dr. Thorsten Lehr
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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