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。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
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
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引用次数: 0

摘要

背景和目的:DT-678是一种新型抗血小板原药,能够在暴露于谷胱甘肽时释放氯吡格雷(AM)的抗血小板活性代谢物。在这项研究中,我们调查了导致急性冠状动脉综合征(ACS)患者氯吡格雷治疗时血小板高反应性(HTPR)的因素,并评估了 DT-678 克服 HTPR 的能力:实验方法:共招募了300名连续使用P2Y12受体抑制剂的ACS患者,并进行了CYP2C19等位基因的基因分型。在服用 600 毫克氯吡格雷前后抽取血样。测定血小板反应指数(PRI)和血浆 AM 浓度,并根据其 CYP2C19 基因型进行分组。将 DT-678 应用于体内全血样本以检测其抑制作用。为了进一步检验 DT-678 在体内的抗血小板效果,在一项 I 期临床试验中招募了 20 名健康受试者,每人单次服用 3 毫克 DT-678 或 75 毫克氯吡格雷。比较了不同 CYP2C19 基因型组的药代动力学和药效学:统计分析显示,CYP2C19基因型、体重指数、高尿酸血症和基线PRI与ACS患者发生氯吡格雷HTPR的较高风险显著相关。无论CYP2C19基因型如何,体内添加DT-678都能降低基线PRI,从而克服氯吡格雷HTPR。这一观察结果在接受3毫克DT-678治疗的健康志愿者身上得到了进一步证实:这些结果表明,DT-678能有效克服中国ACS患者因遗传和/或临床因素导致的氯吡格雷HTPR,显示了其改善抗血小板治疗的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
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.
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