Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers.
Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers.
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新型 P2Y12 拮抗剂维卡格雷在中国健康志愿者中的耐受性、药代动力学和药效学评价
DOI：
10.3389/fphar.2018.00643
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发表时间：
2018
影响因子：
5.6
通讯作者：
Ding Y
中科院分区：
文献类型：
--
作者：
Li X;Liu C;Zhu X;Wei H;Zhang H;Chen H;Chen G;Yang D;Sun H;Shen Z;Zhang Y;Li W;Yang J;Liu Y;Lai X;Gong Y;Liu X;Li Y;Zhong D;Niu J;Liu B;Ding Y
研究背景：维格瑞是一种新型抗血小板药物，其水解途径与氯吡格雷相同，而不是通过CYP 2C 19酶。本文报道了在中国健康志愿者中首次进行的不同剂量的维格瑞洛的耐受性、药代动力学和药效学的临床试验，并与氯吡格雷进行了比较。方法：本研究分两部分进行。研究I是一项剂量递增（5-15 mg）研究。对于每种剂量，15名参与者被随机分为三组（总共n = 45）; 9名参与者给予vicagrel，3名给予氯吡格雷，3名给予安慰剂。研究II是在15名健康受试者中进行的，目的是评估vicagrel和阿司匹林之间的相互作用。采用LC-MS/MS法测定了维格瑞和氯吡格雷代谢产物的血浆浓度。使用VerifyNow-P2 Y12试验评估血小板聚集。结果：健康志愿者服用维格瑞（5-15 mg/d）10天或加用阿司匹林耐受性良好。活性代谢产物的暴露量在剂量范围内成比例增加，并且高于氯吡格雷（约10倍）。IPA给药75 mg氯吡格雷的水平介于5 mg和10 mg vicagrel的反应之间。在单次负荷剂量的vicagrel（30 mg）和每日一次维持剂量（7.5 mg）8天后，血小板聚集的最大抑制作用与联合使用vicagrel和阿司匹林（100 mg/天）相似。结论：口服vicagrel表现出良好的安全性和良好的抗血小板活性，这可能是一个有前途的P2 Y12拮抗剂作为抗血小板药物，并可以在II/III期研究中进一步开发，并上市以满足心血管疾病的未满足的医疗需求。该研究在http://www.chictr.org.cn（ChiCTR-IIR-16009260）上注册。
Background: Vicagrel is a novel anti-platelet drug and hydrolyzed to the same intermediate as clopidogrel via esterase, instead of CYP2C19. Here we report the first clinical trial on the tolerability, pharmacokinetics and pharmacodynamics of different doses of vicagrel, and comparison with clopidogrel in healthy Chinese volunteers. Methods: This study was conducted in two parts. Study I was a dose-escalating (5–15 mg) study. For each dose, 15 participants were randomized into three groups (total n = 45); nine participants were given vicagrel, three were given clopidogrel, and three were given a placebo. Study II was conducted to assess interactions between vicagrel and aspirin in 15 healthy participants. The plasma concentrations of the metabolites of vicagrel and clopidogrel were determined using a LC-MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y12 assay. Results: Vicagrel (5–15 mg per day) dosing for 10 days or addition of aspirin was well tolerated in healthy volunteers. The exposure of the active metabolite increased proportionally across the dose range and was higher (~10-fold) than clopidogrel. The levels of IPA dosing 75 mg clopidogrel were between the responses of 5 mg and 10 mg vicagrel. After a single loading dose of vicagrel (30 mg) and a once-daily maintenance dose (7.5 mg) for 8 days, the maximum inhibition of platelet aggregation was similar to that seen with the combined use of vicagrel and aspirin (100 mg/day). Conclusion: Oral vicagrel demonstrated a favorable safety profile and excellent anti-platelet activity, which could be a promising P2Y12 antagonist as anti-platelet drug and can be further developed in phase II/III studies, and marketing for the unmet medical needs of cardiovascular diseases. The study was registered at http://www.chictr.org.cn (ChiCTR-IIR-16009260).
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影响因子：
37.8
作者：
Price, Matthew J.;Angiolillo, Dominick J.;Topol, Eric J.
通讯作者：
Topol, Eric J.
影响因子：
2.9
作者：
Anderson, Shawn D.;Shah, Niren K.;Epstein, Benjamin J.
通讯作者：
Epstein, Benjamin J.
影响因子：
3.9
作者：
Hagihara, Katsunobu;Kazui, Miho;Kurihara, Atsushi
通讯作者：
Kurihara, Atsushi
影响因子：
6.1
作者：
Lazar, Lawrence D.;Lincoff, A. Michael
通讯作者：
Lincoff, A. Michael
影响因子：
3.9
作者：
Djebli, Nassim;Fabre, David;Hurbin, Fabrice
通讯作者：
Hurbin, Fabrice