Adam Lauver, PhD

Cardiovascular diseases remain the leading cause of death in the United States. Dual anti-platelet therapy using aspirin and a P2Y12 antagonist, such as clopidogrel, is the standard therapeutic intervention in patients with coronary artery disease. The efficacy of this treatment strategy has been demonstrated in numerous clinical trials; however, like many antithrombotic therapies it is frequently associated with adverse bleeding events. Furthermore, clopidogrel-treated patients demonstrate significant variability in their responses and frequent drug-drug interactions occur. These factors limit clopidogrel’s use and are due to a complex bioactivation process which results in the formation of at least a dozen different metabolites that are thought to possess actions beyond the inhibition of platelets. However, due to a lack of stable synthetic metabolite standards for pharmacological evaluation, a specific comparison of the biological actions clopidogrel metabolites has not been performed. Based on the available literature and this study’s preliminary data, it is proposed that the observed adverse bleeding effects are mediated, in part, by the action of clopidogrel metabolites at sites other than the platelet P2Y12 receptor. To investigate, this project has developed DT678, a disulfide prodrug of the sole clopidogrel metabolite responsible for the inhibition of P2Y12. The data demonstrates that at equally effective antiplatelet doses, DT678 has a reduced bleeding risk compared to clopidogrel and it is likely that the P2Y12-independent effects of the other metabolites account for the differences observed. The overall objectives of this project are to compare the actions of clopidogrel and DT678 on platelet activation and vascular function. The results of this project will contribute significantly to the knowledge of the bleeding side-effects associated with antiplatelet drug therapy and therefore improve clinical outcomes in patients at high risk for thrombotic events.