Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, in healthy subjects
Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, in healthy subjects
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DOI：
10.1007/s00228-009-0778-5
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发表时间：
2010-05-01
影响因子：
2.9
通讯作者：
Butler, Kathleen
中科院分区：
文献类型：
--
作者：
Teng, Renli;Butler, Kathleen
目的替格瑞洛（Ticagrelor，AZD 6140）是第一个可逆结合口服P2 Y（12）受体拮抗剂，用于减少急性冠脉综合征患者的临床血栓事件。我们研究的目的是确定替格瑞洛单次递增剂量在健康受试者中的作用。方法在两项随机、双盲、安慰剂对照的单次递增剂量研究中，健康受试者接受口服剂量0.1-100 mg或安慰剂（n=25）和30-400 mg或安慰剂（n= 13）。max）1.3-2 h]，其主要（活性）代谢产物AR-C124910 XX的形成也是如此（t（max）1.5-3 h）。对于替格瑞洛和AR-C124910 XX，在研究的剂量范围内，血浆峰浓度（C-max）和从时间0至无穷大的血浆浓度-时间曲线下面积（AUC（0-无穷大））以明显与剂量成比例的方式增加，表明药代动力学呈线性。替格瑞洛的平均终末期半衰期（t（1/2））约为7-8.5 h，AR-C124910 XX约为8.5-10 h; AR-C124910 XX暴露量约为替格瑞洛的三分之一。血小板聚集（IPA）的抑制是剂量相关的，几乎完全在2小时（平均88-95%;最终程度，与20 μ M腺苷二磷酸ADP）在100-400 mg的剂量。结论线性和可预测的替格瑞洛和AR-C124910 XX的药代动力学观察。在2-12小时内保持一致的高IPA，从给药后约12小时开始随着血浆浓度下降而逐渐降低，表明IPA是可逆的。替格瑞洛耐受性良好，未观察到严重或剂量相关的不良事件或实验室值的显著变化。
Purpose Ticagrelor (AZD6140) is the first reversibly binding oral P2Y(12) receptor antagonist in development for reduction of clinical thrombotic events in patients with acute coronary syndromes. The purpose of our studies was to determine the effect of single-ascending doses of ticagrelor in healthy subjects.Methods In two randomised, double-blind, placebo-controlled single ascending dose studies, healthy subjects received oral doses of 0.1-100 mg or placebo (n=25) and 30-400 mg or placebo (n= 13).Results Absorption of ticagrelor was rapid [median time to peak plasma concentration (t(max)) 1.3-2 h], as was the formation of its main (active) metabolite, AR-C124910XX (t(max) 1.5-3 h). For both ticagrelor and AR-C124910XX, the peak plasma concentration (C-max) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) increased in an apparently dose-proportional manner over the dose range studied, indicating linear pharmacokinetics. The mean terminal-phase half-life (t(1/2)) was approximately 7-8.5 h for ticagrelor and 8.5-10 h for AR-C124910XX; AR-C124910XX exposure was approximately one third that of ticagrelor. Inhibition of platelet aggregation (IPA) was dose related and was nearly complete at 2 h (mean 88-95%; final extent, with 20 mu M adenosine diphosphate ADP) at doses of 100-400 mg.Conclusion Linear and predictable pharmacokinetics of ticagrelor and AR-C124910XX were observed. A consistent and high IPA was maintained over 2-12 h, gradually decreasing with declining plasma concentration starting around 12 h post-dose, indicating that the IPA is reversible. Ticagrelor was well tolerated, with no serious or dose-related adverse events or notable changes in laboratory values observed.