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Identifying clinically relevant sources of variability: The clopidogrel challenge
S Samant1, X L Jiang1, L A Peletier2
1Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, Florida, USA.
Clinical Pharmacology and Therapeutics
|August 25, 2016
Summary
Clopidogrel dosing needs adjustment for individuals with specific CYP2C19 gene variants and obesity. Personalized clopidogrel therapy can improve antiplatelet treatment effectiveness and reduce adverse events.
Area of Science:
- Pharmacology
- Pharmacogenomics
- Clinical Pharmacy
Background:
- Clopidogrel's standard dosing shows high interindividual variability in patient outcomes.
- Factors like CYP2C19 polymorphisms, obesity, age, diabetes, and drug interactions contribute to treatment failure.
Purpose of the Study:
- To conduct a mechanism-based pharmacokinetic/pharmacodynamic analysis of clopidogrel.
- To characterize changes in platelet reactivity considering genetic and demographic factors.
Main Methods:
- Integrated in vitro enzyme kinetics, physiological, genetic, and demographic data.
- Performed a mechanism-based pharmacokinetic/pharmacodynamic analysis.
Main Results:
- Higher clopidogrel maintenance doses are needed for CYP2C19 intermediate and poor metabolizers.
- Obese individuals require further dose increases within each CYP2C19 phenotype group.
- Interindividual differences in absorption and CES1 activity impact active metabolite concentrations and platelet reactivity.
Conclusions:
- CYP2C19 genotype and obesity are key determinants of clopidogrel response.
- Personalized dosing strategies are essential for optimizing clopidogrel's antiplatelet efficacy.
- Understanding absorption and CES1 activity can further refine clopidogrel therapy.
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