Zhihao Liu, Shengcong Liu, Yanjun Gong, Xiying Chi, Ting Wang, Fangfang Fan, Chenxue Qu, Yaxin Lou, Long Zhang, Bin Zhang, Fan Yang, Momin Mohetaboer, Jie Wang, Lin Qiu, Linzi Miao, Yao Lu, Ran You, Pengkang He, Yuxi Li, Tieci Yi, Haoyu Weng, Yulong Xia, Chunyan Wang, Qiuping Shi, Zhi Wang, Yimeng Jiang, Yinjuan Li, Chunyu Han, Yu Wang, Xinghe Wang, Caixia Yang, Y Eugene Chen, Daniel T Eitzman, Haoming Zhang, Jianping Li
{"title":"首次在急性冠脉综合征患者和健康志愿者中开展人体研究,评估氯吡格雷共轭物 DT-678 的抗血小板特性。","authors":"Zhihao Liu, Shengcong Liu, Yanjun Gong, Xiying Chi, Ting Wang, Fangfang Fan, Chenxue Qu, Yaxin Lou, Long Zhang, Bin Zhang, Fan Yang, Momin Mohetaboer, Jie Wang, Lin Qiu, Linzi Miao, Yao Lu, Ran You, Pengkang He, Yuxi Li, Tieci Yi, Haoyu Weng, Yulong Xia, Chunyan Wang, Qiuping Shi, Zhi Wang, Yimeng Jiang, Yinjuan Li, Chunyu Han, Yu Wang, Xinghe Wang, Caixia Yang, Y Eugene Chen, Daniel T Eitzman, Haoming Zhang, Jianping Li","doi":"10.1111/bph.17355","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and purpose: </strong>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.</p><p><strong>Experimental approach: </strong>A total of 300 consecutive ACS patients naive to P2Y<sub>12</sub> 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.</p><p><strong>Key results: </strong>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.</p><p><strong>Conclusion and implications: </strong>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.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The first in-human study to evaluate the antiplatelet properties of the clopidogrel conjugate DT-678 in acute coronary syndrome patients and healthy volunteers.\",\"authors\":\"Zhihao Liu, Shengcong Liu, Yanjun Gong, Xiying Chi, Ting Wang, Fangfang Fan, Chenxue Qu, Yaxin Lou, Long Zhang, Bin Zhang, Fan Yang, Momin Mohetaboer, Jie Wang, Lin Qiu, Linzi Miao, Yao Lu, Ran You, Pengkang He, Yuxi Li, Tieci Yi, Haoyu Weng, Yulong Xia, Chunyan Wang, Qiuping Shi, Zhi Wang, Yimeng Jiang, Yinjuan Li, Chunyu Han, Yu Wang, Xinghe Wang, Caixia Yang, Y Eugene Chen, Daniel T Eitzman, Haoming Zhang, Jianping Li\",\"doi\":\"10.1111/bph.17355\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and purpose: </strong>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.</p><p><strong>Experimental approach: </strong>A total of 300 consecutive ACS patients naive to P2Y<sub>12</sub> 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.</p><p><strong>Key results: </strong>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.</p><p><strong>Conclusion and implications: </strong>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.</p>\",\"PeriodicalId\":9262,\"journal\":{\"name\":\"British Journal of Pharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-10-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"British Journal of Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/bph.17355\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"British Journal of Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/bph.17355","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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 P2Y12 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.
期刊介绍:
The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries.
Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues.
In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.