The first in‐human study to evaluate the antiplatelet properties of the clopidogrel conjugate DT‐678 in acute coronary syndrome patients and healthy volunteers

Background and Purpose DT‐678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on‐treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT‐678 to overcome HTPR. Experimental Approach A total of 300 consecutive ACS patients naive to P2Y 12 receptor inhibitors were recruited and genotyped for CYP2C19 alleles. Blood samples were drawn before and after administration of 600‐mg clopidogrel. Platelet reactivity index (PRI) and plasma AM concentrations were determined and grouped according to their CYP2C19 genotypes. DT‐678 was applied ex vivo to whole blood samples to examine its inhibitory effects. To further examine the antiplatelet effectiveness of DT‐678 in vivo, 20 healthy human subjects were recruited in a Phase I clinical trial, and each received a single dose of either 3‐mg DT‐678 or 75‐mg clopidogrel. The pharmacokinetics and pharmacodynamics in different CYP2C19 genotype groups were compared. Key Results Statistical analyses revealed that CYP2C19 genotype, body mass index, hyperuricaemia, and baseline PRI were significantly associated with a higher risk of clopidogrel HTPR in ACS patients. The addition of DT‐678 ex vivo decreased baseline PRI regardless of CYP2C19 genotypes, overcoming clopidogrel HTPR. This observation was further confirmed in healthy volunteers receiving 3 mg of DT‐678. Conclusion and Implications These results suggest that DT‐678 effectively overcomes clopidogrel HTPR resulting from genetic and/or clinical factors in Chinese ACS patients, demonstrating its potential to improve antiplatelet therapy.