Abstract 19851: Phenotyping or Genotyping to capture Clopidogrel Active Metabolite Generation.
Introduction: To assure an efficient and safe clopidogrel therapy in the individual patient, two different strategies have been proposed to optimize the response to clopidogrel. However, whether (1) phenotyping (platelet function testing) or (2) genotyping is the most appropriate strategy to tailor antiplatelet therapy remains to be established. In the present study we sought to estimate the percentage of variability in active metabolite generation that is captured by platelet function testing versus a panel of genetic polymorphisms.
Methods: Clopidogrel-naive patients (n=54) received a 600mg loading dose of clopidogrel. Information on medication usage and clinical variables was obtained from medical records. For pharmacokinetic analysis, blood was drawn at sequential time-points and peak plasma levels of the active metabolite of clopidogrel (AMC) were quantified with LC-MS/MS. Platelet function testing using the VerifyNow P2Y12-assay was performed at 6h after clopidogrel loading. Genetic testing included a panel of genetic variants of the MDR1-gene (G2677T/A, C3435T, C1236T) and the cytochrome P450 enzymes CYP3A4 (A290G), CYP3A5 (A6986G), CYP2C9 (*2 and *3), and CYP2C19 (*2, *3 and *17).
Results: The MDR1 C1236T, CYP2C9*2, and CYP2C19*2 genetic variants were associated with plasma levels of the AMC in univariate analysis. Together, these gene variants explained 22.1% (p=0.010) of the variability in the peak plasma AMC-levels, increasing to 38.3% (p=0.008) after adding the use of medication interfering with generation of the AMC. The VerifyNow P2Y12-assay alone could explain 37.4% (p<0.001) of the variance in plasma levels of the AMC, compared to 50.1% (p<0.001) when medication usage was considered as well. Finally, clinical variables associated with AMC-levels were taken into account. The percentage of variability in AMC levels that could be clarified was 52.1% (p=0.010) for genetic variants, compared to 57.3% (p<0.001) for the VerifyNow P2Y12-assay.
Conclusions: Platelet function testing captures a larger degree of the variability in active clopidogrel metabolite generation, suggesting that a phenotypic approach is preferable over determining the genotypes tentatively acknowledged to affect clopidogrel metabolism.
- © 2010 by American Heart Association, Inc.