Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug-Drug-Gene Interaction Predictions

The antiplatelet agent clopidogrel is listed by the FDA as a strong clinical index inhibitor of cytochrome P450 (CYP) 2C8 and weak clinical inhibitor of CYP2B6. Moreover, clopidogrel is a substrate of-among others-CYP2C19 and CYP3A4. This work presents the development of a whole-body physiologically...

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Published in:Pharmaceutics 2022-04, Vol.14 (5), p.915
Main Authors: Loer, Helena Leonie Hanae, Türk, Denise, Gómez-Mantilla, José David, Selzer, Dominik, Lehr, Thorsten
Format: Article
Language:English
Subjects:
clopidogrel
clopidogrel active metabolite
clopidogrel acyl glucuronide
Digitization
Drug dosages
drug–drug interaction (DDI)
drug–gene interaction (DGI)
Enzymes
Metabolism
Metabolites
Open systems
Pharmacokinetics
Pharmacology
physiologically based pharmacokinetic (PBPK) modeling
Plasma
Sensitivity analysis
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Summary:The antiplatelet agent clopidogrel is listed by the FDA as a strong clinical index inhibitor of cytochrome P450 (CYP) 2C8 and weak clinical inhibitor of CYP2B6. Moreover, clopidogrel is a substrate of-among others-CYP2C19 and CYP3A4. This work presents the development of a whole-body physiologically based pharmacokinetic (PBPK) model of clopidogrel including the relevant metabolites, clopidogrel carboxylic acid, clopidogrel acyl glucuronide, 2-oxo-clopidogrel, and the active thiol metabolite, with subsequent application for drug-gene interaction (DGI) and drug-drug interaction (DDI) predictions. Model building was performed in PK-Sim using 66 plasma concentration-time profiles of clopidogrel and its metabolites. The comprehensive parent-metabolite model covers biotransformation via carboxylesterase (CES) 1, CES2, CYP2C19, CYP3A4, and uridine 5'-diphospho-glucuronosyltransferase 2B7. Moreover, CYP2C19 was incorporated for normal, intermediate, and poor metabolizer phenotypes. Good predictive performance of the model was demonstrated for the DGI involving CYP2C19, with 17/19 predicted DGI AUC and 19/19 predicted DGI C ratios within 2-fold of their observed values. Furthermore, DDIs involving bupropion, omeprazole, montelukast, pioglitazone, repaglinide, and rifampicin showed 13/13 predicted DDI AUC and 13/13 predicted DDI C ratios within 2-fold of their observed ratios. After publication, the model will be made publicly accessible in the Open Systems Pharmacology repository.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics14050915