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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MDPI AG
2022-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/5/915 |
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| author | Helena Leonie Hanae Loer Denise Türk José David Gómez-Mantilla Dominik Selzer Thorsten Lehr |
| author_facet | Helena Leonie Hanae Loer Denise Türk José David Gómez-Mantilla Dominik Selzer Thorsten Lehr |
| author_sort | Helena Leonie Hanae Loer |
| collection | DOAJ |
| description | 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<sup>®</sup> 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<sub>last</sub> and 19/19 predicted DGI C<sub>max</sub> ratios within 2-fold of their observed values. Furthermore, DDIs involving bupropion, omeprazole, montelukast, pioglitazone, repaglinide, and rifampicin showed 13/13 predicted DDI AUC<sub>last</sub> and 13/13 predicted DDI C<sub>max</sub> ratios within 2-fold of their observed ratios. After publication, the model will be made publicly accessible in the Open Systems Pharmacology repository. |
| first_indexed | 2024-03-10T03:08:15Z |
| format | Article |
| id | doaj.art-1d81298bd9614cba9f1a4ac9ab5723d7 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T03:08:15Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-1d81298bd9614cba9f1a4ac9ab5723d72023-11-23T12:36:26ZengMDPI AGPharmaceutics1999-49232022-04-0114591510.3390/pharmaceutics14050915Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction PredictionsHelena Leonie Hanae Loer0Denise Türk1José David Gómez-Mantilla2Dominik Selzer3Thorsten Lehr4Department of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, GermanyDepartment of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, GermanyTranslational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, 55216 Ingelheim, GermanyDepartment of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, GermanyDepartment of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, GermanyThe 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<sup>®</sup> 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<sub>last</sub> and 19/19 predicted DGI C<sub>max</sub> ratios within 2-fold of their observed values. Furthermore, DDIs involving bupropion, omeprazole, montelukast, pioglitazone, repaglinide, and rifampicin showed 13/13 predicted DDI AUC<sub>last</sub> and 13/13 predicted DDI C<sub>max</sub> ratios within 2-fold of their observed ratios. After publication, the model will be made publicly accessible in the Open Systems Pharmacology repository.https://www.mdpi.com/1999-4923/14/5/915physiologically based pharmacokinetic (PBPK) modelingclopidogrelclopidogrel acyl glucuronideclopidogrel active metabolitedrug–gene interaction (DGI)drug–drug interaction (DDI) |
| spellingShingle | Helena Leonie Hanae Loer Denise Türk José David Gómez-Mantilla Dominik Selzer Thorsten Lehr Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction Predictions Pharmaceutics physiologically based pharmacokinetic (PBPK) modeling clopidogrel clopidogrel acyl glucuronide clopidogrel active metabolite drug–gene interaction (DGI) drug–drug interaction (DDI) |
| title | Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction Predictions |
| title_full | Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction Predictions |
| title_fullStr | Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction Predictions |
| title_full_unstemmed | Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction Predictions |
| title_short | Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction Predictions |
| title_sort | physiologically based pharmacokinetic pbpk modeling of clopidogrel and its four relevant metabolites for cyp2b6 cyp2c8 cyp2c19 and cyp3a4 drug drug gene interaction predictions |
| topic | physiologically based pharmacokinetic (PBPK) modeling clopidogrel clopidogrel acyl glucuronide clopidogrel active metabolite drug–gene interaction (DGI) drug–drug interaction (DDI) |
| url | https://www.mdpi.com/1999-4923/14/5/915 |
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