Abstract T MP108: A Concentration Response Relationship Between the Active Metabolite of Clopidogrel and its Antiplatelet Activity

Abstract

Background: Variability in antiplatelet response to clopidogrel is reported to be due, in part, to the reduced ability to metabolize clopidogrel to its active form. This can be a result of a genetic difference in metabolizer status or to drug interactions which can cause inhibition of either the CYP2C19 or CYP3A4 P450 isoenzymes. Although up to this point it has remained unclear whether there is a concentration dependent relationship between clopidogrel's active thiol metabolite and its antiplatelet effects and whether there is a threshold concentration of the active metabolite (AM) needed to produce an adequate antiplatelet effect, this 3-arm, complete crossover study demonstrates a statistical relationship between AM concentrations and antiplatelet response. Methods: Fourteen healthy male volunteers took clopidogrel doses of 25 mg, 50 mg, and 75 mg. Participants were excluded for tobacco, illicit substance, and alcohol use. AM concentrations were measured using liquid chromatography-mass spectrometry over a 4 hour period and an area under the curve (AUC) was calculated. Results: The median baseline whole blood platelet aggregation value was 8 Ω (IQR=7-8.5 Ω) and responsiveness to clopidogrel was defined as <6 Ω and a ≥60% decrease from baseline. Using a receiver operating characteristic (ROC) curve the optimal AUC 0-4 was found to be 784ng*min/mL. Sensitivity was 92.0% (95% CI: 48.0-100.0%) and specificity was 71.4% (95% CI: 46.4-85.7%). Area under the ROC curve was 84.0% (95% CI: 73.0-95.0%, p=1.867e-5) demonstrating statistical validity of the estimates of the AM threshold concentration needed to inhibit platelet aggregation. A Bayesian breakpoint analysis found the optimal threshold AUC to be in a range from 732-882 ng*min/mL. Conclusions: These findings could make it possible for clinicians to immediately tailor antiplatelet therapy to individual patients by measuring AM levels after the first dose of clopidogrel, conceivably preventing a secondary event at a time when risk is the highest. Additionally, research is ongoing to explore whether disease states commonly seen in stroke patients, such as diabetes, change the amount of the AM produced or whether they may actually result in a shift of the concentration response curve.