Li Xiaojiao, Liu Cai, Zhu Xiaoxue, Wei Haijing, Zhang Hong, Chen Hong, Chen Guiling, Yang Deming, Sun Hongbin, Shen Zhenwei, Zhang Yifan, Li Wei, Yang Jin, Liu Yongqiang, Lai Xiaojuan, Gong Yanchun, Liu Xuefang, Li Yongguo, Zhong Dafang, Niu Junqi, Liu Bin, Ding Yanhua
Phase I Clinical Trial Unit, First Hospital, Jilin University, Jilin, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Front Pharmacol. 2018 Jun 20;9:643. doi: 10.3389/fphar.2018.00643. eCollection 2018.
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. 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 = 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. 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). 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).
维卡格雷是一种新型抗血小板药物，可通过酯酶水解为与氯吡格雷相同的中间体，而非通过细胞色素P450 2C19（CYP2C19）。在此，我们报告了第一项关于不同剂量维卡格雷的耐受性、药代动力学和药效学的临床试验，并在健康中国志愿者中与氯吡格雷进行了比较。本研究分为两个部分。研究I是一项剂量递增（5 - 15毫克）研究。对于每个剂量，15名参与者被随机分为三组（共45名）；9名参与者给予维卡格雷，3名给予氯吡格雷，3名给予安慰剂。研究II旨在评估15名健康参与者中维卡格雷与阿司匹林之间的相互作用。使用液相色谱 - 串联质谱法（LC - MS/MS）测定维卡格雷和氯吡格雷代谢物的血浆浓度。使用VerifyNow - P2Y12检测法评估血小板聚集情况。健康志愿者对维卡格雷（每日5 - 15毫克）给药10天或加用阿司匹林耐受性良好。活性代谢物的暴露量在整个剂量范围内成比例增加，且比氯吡格雷高（约10倍）。服用75毫克氯吡格雷时的IPA水平介于5毫克和10毫克维卡格雷的反应之间。在单次负荷剂量维卡格雷（30毫克）和每日一次维持剂量（7.5毫克）给药8天后，血小板聚集的最大抑制作用与维卡格雷和阿司匹林联合使用（每日100毫克）时相似。口服维卡格雷显示出良好的安全性和出色的抗血小板活性，作为抗血小板药物可能是一种有前景的P2Y12拮抗剂，可在II/III期研究中进一步开发，并用于满足心血管疾病未满足的医疗需求。该研究已在http://www.chictr.org.cn（ChiCTR - IIR - 16009260）注册。
