Peking University Third Hospital, Beijing, China.
Clin Drug Investig. 2012 Feb 1;32(2):87-97. doi: 10.2165/11595930-000000000-00000.
Ticagrelor (Brilinta™) is an antithrombotic agent that reversibly binds to P2Y(12) receptors and inhibits adenosine diphosphate-induced platelet aggregation. Ticagrelor has undergone evaluation in the phase III PLATO trial, which enrolled 18 624 patients with acute coronary syndromes (ACS) from 43 countries, and 6% of patients were Asian. Subsequently, ticagrelor has now been approved in more than 40 countries for the prevention of atherothrombotic events in adult patients with ACS. Gene polymorphisms in drug-metabolizing enzymes may vary with ethnicity, and can alter drug exposure, potentially impacting drug efficacy and/or tolerability. The objectives of this study were to assess the pharmacokinetic parameters of ticagrelor and its active metabolite AR-C124910XX, and the safety and tolerability of ticagrelor in healthy Chinese subjects, following single and multiple oral doses of ticagrelor.
This trial was an open-label, sequential, two-cohort, single-centre study investigating 90 mg and 180 mg doses of ticagrelor in healthy Chinese subjects. On day 1, 12 subjects received a single oral dose of ticagrelor 90 mg. Following a 2-day washout period, ticagrelor was administered twice daily (90 mg twice daily) on days 4-9 and as a single dose on day 10. After completion of this phase, additional subjects (n = 14) were recruited into the ticagrelor 180 mg group, and received ticagrelor 180 mg under the same dosing schedule. On days 1 and 10 of both dosing schedules, blood samples for pharmacokinetic analyses were collected for 72 hours.
Following single and multiple doses at both dose levels, ticagrelor was rapidly absorbed (median time [t(max)] to reach maximum plasma concentration [C(max)] 2 hours) with a mean elimination half-life (t(1/2;)) of 10.9-14.9 hours. AR-C124910XX was rapidly formed (median t(max) 2.0-3.0 hours; mean t(1/2;) 9.1-11.9 hours). Steady-state concentrations of ticagrelor and AR-C124910XX were rapidly established with both dosing regimens. Both parent and metabolite exhibited linear and predictable pharmacokinetics with single and multiple dosing as mean minimum plasma concentration (C(min)), C(max) and area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) were approximately 2-fold higher with ticagrelor 180 mg (e.g. multiple-dosing, geometric mean [% coefficient of variation]: C(max) 1973 [27] and AUC(∞) 18 035 [46]) versus 90 mg (e.g. multiple dosing: C(max) 915 [32] and AUC(∞) 7168 [35]) dosing regimens. Overall, ticagrelor was generally well tolerated in healthy Chinese subjects. Two subjects discontinued in the ticagrelor 90 mg group due to elevated serum levels of ALT and AST. Mild ticagrelor-associated adverse events were seen: bleeding events (90 mg: epistaxis n = 1; 180 mg: gingival bleeding n = 1) and dyspnoea (180 mg: n = 3).
In healthy Chinese subjects, ticagrelor and AR-C124910XX pharmacokinetics were linear and predictable. Although ticagrelor and AR-C124910XX exposure at steady state were found to be slightly higher in Chinese subjects, these results were broadly similar to previous data in Caucasian subjects. Overall, ticagrelor was well tolerated in healthy Chinese subjects.
ClinicalTrials.gov identifier: NCT00721448.
替格瑞洛（Brilinta™）是一种抗血栓药物，可可逆地结合 P2Y(12)受体并抑制二磷酸腺苷诱导的血小板聚集。替格瑞洛已在 III 期 PLATO 试验中进行了评估，该试验纳入了来自 43 个国家的 18624 例急性冠脉综合征（ACS）患者，其中 6%为亚洲人。随后，替格瑞洛已在 40 多个国家批准用于预防成人 ACS 患者的动脉粥样硬化血栓事件。药物代谢酶的基因多态性可能因种族而异，并能改变药物暴露量，可能影响药物疗效和/或耐受性。本研究的目的是评估替格瑞洛及其活性代谢物 AR-C124910XX 的药代动力学参数，以及替格瑞洛在健康中国受试者中的安全性和耐受性，在这些受试者中，替格瑞洛采用单剂量和多剂量口服。
本试验是一项开放标签、序贯、两队列、单中心研究，在中国健康受试者中调查了 90mg 和 180mg 剂量的替格瑞洛。在第 1 天，12 名受试者接受了替格瑞洛 90mg 的单次口服剂量。在 2 天的洗脱期后，替格瑞洛在第 4-9 天每日两次（90mg 每日两次）给药，第 10 天单次给药。在这一阶段完成后，另外 14 名受试者（n=14）被招募到替格瑞洛 180mg 组，并在相同的给药方案下接受替格瑞洛 180mg。在两种给药方案的第 1 天和第 10 天，采集血样进行 72 小时的药代动力学分析。
在单剂量和双剂量给药水平下，替格瑞洛吸收迅速（达到最大血浆浓度[Cmax]的中位数时间[t(max)]为 2 小时），平均消除半衰期（t(1/2;)为 10.9-14.9 小时。AR-C124910XX 迅速形成（中位数 t(max)为 2.0-3.0 小时；平均 t(1/2;)为 9.1-11.9 小时）。替格瑞洛和 AR-C124910XX 的稳态浓度迅速建立，两种给药方案均如此。无论是单剂量还是多剂量，替格瑞洛和代谢物的最小血浆浓度（C(min)）、最大血浆浓度（C(max)）和零至无穷时的血浆浓度-时间曲线下面积（AUC(∞)）都呈线性和可预测性，与替格瑞洛 180mg 相比（例如，多剂量，几何平均值[％变异系数]：C(max)1973[27]和 AUC(∞)18035[46]），替格瑞洛 90mg 的结果（例如，多剂量：C(max)915[32]和 AUC(∞)7168[35]）大约高 2 倍。总体而言，替格瑞洛在健康中国受试者中通常具有良好的耐受性。两名受试者因血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶升高而退出替格瑞洛 90mg 组。轻度替格瑞洛相关不良事件可见：出血事件（90mg：鼻出血 1 例；180mg：牙龈出血 1 例）和呼吸困难（180mg：3 例）。
在中国健康受试者中，替格瑞洛和 AR-C124910XX 的药代动力学呈线性和可预测性。尽管在中国受试者中，替格瑞洛和 AR-C124910XX 的稳态暴露量略高，但这些结果与以前在白种人受试者中的数据基本一致。总体而言，替格瑞洛在健康中国受试者中耐受性良好。
ClinicalTrials.gov 标识符：NCT00721448。
