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

Abstract

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 AUClast and 19/19 predicted DGI Cmax ratios within 2-fold of their observed values. Furthermore, DDIs involving bupropion, omeprazole, montelukast, pioglitazone, repaglinide, and rifampicin showed 13/13 predicted DDI AUClast and 13/13 predicted DDI Cmax ratios within 2-fold of their observed ratios. After publication, the model will be made publicly accessible in the Open Systems Pharmacology repository.

The Role of Dual Antiplatelet in Stent-Assisted Coiling in Wide-Neck Aneurysm

“…The active metabolite permanently blocks the platelet ADP P2Y12 receptor, which causes impaired platelet function. 5,6,9,10 Thus, patients will experience treatment failure.…”

“…At this point, genetic testing is not the answer to explain the poor antiplatelet response to clopidogrel therapy. 9,10 There are recommendations about the role of genetic testing as a routine treatment or approach to safety and pharmacological efficacy. The American Heart Association and the American College of Cardiology Foundation have found that there are clinical problems, such as a lack of information that routine testing improves outcomes for significant subgroups of patients, widespread variability of CYP2C19 gene polymorphisms, high cost, replacement associated with genetic testing, availability of other thienopyridines and P2Y12 ADP receptor antagonists, and using platelet function testing as an alternative to monitoring therapy.…”

“…According to recent research, the first metabolic process involves CYP1A2, CYP2C19, and CYP2B6, while the second metabolic step involves CYP3A, CYP2B6, CYP2C19, and CYP2C9. [6][7][8][9][10][11] Several studies have shown that people respond well to clopidogrel, though the optimal loading and maintenance doses, switching to another thienopyridine with prasugrel and ticagrelor, and the tests used to assess platelet reactivity are still debated. 12…”

Population pharmacokinetic‐pharmacodynamic modeling of clopidogrel for dose regimen optimization based on CYP2C19 phenotypes: A proof of concept study

“…Our novel dosing guideline can be used as a PoC to instigate future exploratory and validation studies to achieve better therapeutic effects in patients with different CYP2C19 phenotypes and baseline PRU levels and provide an alternative personalization strategy in PMs when switching to other antiplatelet drugs is not an option. failure, [6][7][8][9][10] underscoring an urgent need for refined dosing strategies. Evidence from the ADAPT-DES trial indicates that both excessively high and low PRU levels correlate with suboptimal clinical outcomes.…”

“…Consequently, subjects with low CYP2C19 activity exhibit lower clopidogrel H4 concentrations, 6 reduced inhibition of platelet aggregation, and higher rates of thrombotic events than those with normal or high CYP2C19 activity at the same clopidogrel dose. [6][7][8][9][10] Clopidogrel H4 binds irreversibly to P2Y12 receptors on platelet surfaces, 11 which are chemoreceptors for adenosine diphosphate (ADP) belonging to the G i class of G protein-coupled purinergic receptors. [12][13][14] Clopidogrel competes with ADP in binding to P2Y12 receptors and inhibits the activation of the glycoprotein IIb/IIIa complex and ultimately platelet aggregation.…”