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

• Published in: British journal of pharmacology
• Main Authors: Liu, Zhihao, Liu, Shengcong, Gong, Yanjun, Chi, Xiying, Wang, Ting, Fan, Fangfang, Qu, Chenxue, Lou, Yaxin, Zhang, Long, Zhang, Bin, Yang, Fan, Mohetaboer, Momin, Wang, Jie, Qiu, Lin, Miao, Linzi, Lu, Yao, You, Ran, He, Pengkang, Li, Yuxi, Yi, Tieci, Weng, Haoyu, Xia, Yulong, Wang, Chunyan, Shi, Qiuping, Wang, Zhi, Jiang, Yimeng, Li, Yinjuan, Han, Chunyu, Wang, Yu, Wang, Xinghe, Yang, Caixia, Chen, Y Eugene, Eitzman, Daniel T, Zhang, Haoming, Li, Jianping
• Format: Journal Article
• Language: English
• Published: England 04.10.2024
• Subjects: platelet reactivity index; high on‐treatment platelet reactivity; DT‐678; acute coronary syndrome; CYP2C19
• ISSN: 1476-5381
• DOI: 10.1111/bph.17355

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. A total of 300 consecutive ACS patients naive to P2Y 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. 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. 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.