Safety, tolerability, pharmacokinetics and pharmacodynamics of high single-ascending doses of ticagrelor in healthy volunteers
Safety, tolerability, pharmacokinetics and pharmacodynamics of high single-ascending doses of ticagrelor in healthy volunteers
复制标题
DOI：
10.5414/cp201903
复制
发表时间：
2013-10-01
影响因子：
0.8
通讯作者：
Butler, Kathleen
中科院分区：
文献类型：
--
作者：
Teng, Renli;Butler, Kathleen
目的：先前的研究表明替格瑞洛耐受性良好，并且在高达600 mg/天的剂量下表现出线性药代动力学。评估高单次递增剂量的替格瑞洛的安全性、耐受性、药代动力学和药效学（出血时间和肺功能测试），以确定替格瑞洛的最大耐受剂量。材料与方法：本研究为随机、双盲、安慰剂对照研究。计划在替格瑞洛900 mg、1，260 mg和1，620 mg（替格瑞洛：安慰剂比例为6：2）的3个剂量组中招募8名健康志愿者。结果如下：当接受替格瑞洛1，260 mg的6名志愿者中有3名发生中度胃肠道不良事件（AE）时，符合研究停止标准;安慰剂组未观察到任何不良事件。1名接受替格瑞洛1，260 mg的志愿者出现严重AE窦性停搏、高度房室传导阻滞和室性逸搏心律伴晕厥，另1名志愿者出现短暂、轻度呼吸困难。替格瑞洛900 mg耐受性良好。替格瑞洛的总暴露量与剂量成比例增加。替格瑞洛的血浆峰浓度（C-max）没有增加太多，很可能是由于延迟吸收。呼吸参数无相关变化。与安慰剂相比，接受替格瑞洛的患者出血时间延长，接受替格瑞洛1，260 mg的志愿者出血时间长于接受900 mg的志愿者;未报告出血事件。结论：这些结果表明，健康志愿者中替格瑞洛的最大耐受单次剂量为900 mg。
Objective: Previous studies have indicated that ticagrelor is well tolerated and exhibits linear pharmacokinetics up to doses of 600 mg/day. The safety, tolerability, pharmacokinetics and pharmacodynamics (bleeding times and pulmonary function tests) of high single-ascending doses of ticagrelor were assessed to determine the maximum tolerated dose of ticagrelor. Materials and methods: This was a randomized, double-blind, placebo-controlled study. Eight healthy volunteers were planned for enrollment in each of 3 dose groups, ticagrelor 900 mg, 1,260 mg, and 1,620 mg (6 : 2 ratio ticagrelor : placebo). Results: The study stopping criteria were met when 3 of the 6 volunteers receiving ticagrelor 1,260 mg experienced moderate gastrointestinal adverse events (AE); none were observed with placebo. One volunteer receiving ticagrelor 1,260 mg had a serious AE sinus arrest, high-grade atrioventricular block, and ventricular escape rhythm with syncope and another volunteer had brief, mild dyspnea. Ticagrelor 900 mg was well tolerated. Total exposure to ticagrelor increased dose proportionally. Peak plasma concentration (C-max) for ticagrelor did not increase much, most likely due to delayed absorption. There were no relevant changes in respiratory parameters. Bleeding times were prolonged in those receiving ticagrelor with respect to placebo, with longer bleeding times in volunteers receiving ticagrelor 1,260 mg than in volunteers receiving 900 mg; no bleeding events were reported. Conclusion: These results indicate that the maximum tolerated single dose of ticagrelor is 900 mg in healthy volunteers.