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Pharmacokinetics and Tolerability of Single and Multiple Doses of Ticagrelor in Healthy Chinese Subjects An Open-Label, Sequential, Two-Cohort, Single-Centre Study
Li, Haiyan2; Butler, Kathleen; Yang, Li2; Yang, Zhenghua2; Teng, Renli1
刊名CLINICAL DRUG INVESTIGATION
2012
32期:2页:87-97
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Pharmacology & Pharmacy
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]P2Y(12) RECEPTOR ANTAGONIST ; ACUTE CORONARY SYNDROMES ; ETHNIC-DIFFERENCES ; DRUG-METABOLISM ; AZD6140 ; CLOPIDOGREL ; POPULATION ; SAFETY ; CYP3A4 ; PHARMACODYNAMICS
英文摘要

Background and Objectives: Ticagrelor (Brilinta (TM)) 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.

Methods: 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.

Results: 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(infinity)) were approximately 2-fold higher with ticagrelor 180 mg (e.g. multiple-dosing, geometric mean [% coefficient of variation]: C-max 1973 [27] and AUC(infinity) 18 035 [46]) versus 90 mg (e.g. multiple dosing: C-max 915 [32] and AUC(infinity) 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).

Conclusion: 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.

语种英语
WOS记录号WOS:000299600900002
引用统计
被引频次:26[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/68155
专题北京大学第三临床医学院
北京大学第三临床医学院_心血管内科
作者单位1.AstraZeneca LP, Clin Pharmacol, Wilmington, DE 19850 USA
2.Peking Univ, Hosp 3, Beijing 100871, Peoples R China
推荐引用方式
GB/T 7714
Li, Haiyan,Butler, Kathleen,Yang, Li,et al. Pharmacokinetics and Tolerability of Single and Multiple Doses of Ticagrelor in Healthy Chinese Subjects An Open-Label, Sequential, Two-Cohort, Single-Centre Study[J]. CLINICAL DRUG INVESTIGATION,2012,32(2):87-97.
APA Li, Haiyan,Butler, Kathleen,Yang, Li,Yang, Zhenghua,&Teng, Renli.(2012).Pharmacokinetics and Tolerability of Single and Multiple Doses of Ticagrelor in Healthy Chinese Subjects An Open-Label, Sequential, Two-Cohort, Single-Centre Study.CLINICAL DRUG INVESTIGATION,32(2),87-97.
MLA Li, Haiyan,et al."Pharmacokinetics and Tolerability of Single and Multiple Doses of Ticagrelor in Healthy Chinese Subjects An Open-Label, Sequential, Two-Cohort, Single-Centre Study".CLINICAL DRUG INVESTIGATION 32.2(2012):87-97.
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