Dr. Haoming Zhang, Pharmacology Department, The University of Michigan Medical School, USA

Speech Title: Significant Improvement of Pharmacokinetics and Pharmacodynamics of Clopidogrel in AntiPlatelet Therapy by Use of Novel Conjugates

Abstract: Clopidogrel is widely used in anti-platelet therapy to treat patients with acute coronary syndrome. However, it has exhibited clinical limitations such as slow onset and inter-patient variability. The clinical limitations of clopidogrel are in large part due to its poor pharmacokinetics (PK) resulting from inefficient bioactivation by CYP2C19. Patients who carry CYP2C19 loss-of-function genes, which is more common among Asians, have higher risks of mortality and morbidity. To overcome the limitations of clopidogrel, we have developed novel conjugates of clopidogrel that highly effective in inhibiting platelet aggregation without the need for bioactivation by CYP enzymes. We have determined the PK and pharmacodynamics (PD) of a novel conjugate of clopidogrel, referred to as ClopNPT, in animal models. Results from the PK studies showed that ClopNPT released the active metabolite with a time to maximal plasma concentration of < 5 minutes in C57BL/6 mice after either oral or intravenous administration, and plasma concentrations of the active metabolite reached Cmax values of 1242 and 1100 ng/ml after a 10-mg/kg oral dose and a 5-mg/kg intravenous dose, respectively. Furthermore, ClopNPT was highly effective in preventing arterial thrombosis in rabbits and mice after vascular injuries. Formation of occlusive thrombi was prevented by ClopNPT at the 1-mg/kg dose with no significant increase in tongue bleeding time, whereas clopidogrel was ineffective at the same dose. These results suggest that ClopNPT has favorable PK/PD properties that can potentially overcome the attenuated PK properties of clopidogrel and thus significantly improve the efficacy of anti-platelet therapy.