Pharmacodynamics, pharmacokinetics and safety of ticagrelor in Asian patients with stable coronary artery disease

被引:74
作者
Hiasa Y. [1 ]
Teng R. [2 ]
Emanuelsson H. [3 ]
机构
[1] Department of Cardiology, Tokushima Red Cross Hospital, Tokushima
[2] AstraZeneca, Wilmington, DE
[3] AstraZeneca R&D, Pepparredsleden 1, Mölndal
关键词
Japanese; P2Y<sub>12</sub> receptor antagonist; Pharmacodynamics; Pharmacokinetics; Ticagrelor;
D O I
10.1007/s12928-014-0277-1
中图分类号
学科分类号
摘要
This randomized, active-controlled, double-blind study assessed the pharmacodynamics, pharmacokinetics and safety of ticagrelor in Japanese patients and a smaller cohort of non-Japanese Asian patients. The study recruited patients aged 20–80 years who had received aspirin 75–100 mg/day for ≥2 weeks and had percutaneous coronary intervention or acute coronary syndrome >3 months previously. Patients received 4 weeks’ treatment with ticagrelor 45 mg bid, ticagrelor 90 mg bid or clopidogrel 75 mg qd (all with aspirin). The inhibition of platelet aggregation (IPA, final-extent) and pharmacokinetics of ticagrelor were assessed on days 1 and 28. Overall, 139 Asian patients were randomized (ticagrelor 45 mg bid, n = 50; ticagrelor 90 mg bid, n = 43; clopidogrel, n = 46) of whom 118 were Japanese. Mean final-extent IPA was greater with ticagrelor 90 mg bid versus ticagrelor 45 mg bid and with both ticagrelor doses versus clopidogrel. At the end of the dosing interval on day 28, mean final-extent IPA was 10.0 % higher (95 % confidence interval 0.5–19.5 %) for ticagrelor 90 mg bid versus ticagrelor 45 mg bid, 15.1 % higher (5.8–24.4 %) for ticagrelor 45 mg bid versus clopidogrel, and 25.1 % higher (15.5–34.7 %) for ticagrelor 90 mg bid versus clopidogrel. In Japanese patients, exposure to ticagrelor and its active metabolite AR-C124910XX increased dose-proportionally. The safety profile of ticagrelor was consistent with previous studies. Ticagrelor was associated with enhanced IPA versus clopidogrel in Japanese patients. © 2014, Japanese Association of Cardiovascular Intervention and Therapeutics.
引用
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页码:324 / 333
页数:9
相关论文
共 22 条
[1]
Husted S., Emanuelsson H., Heptinstall S., Sandset P.M., Wickens M., Peters G., Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y<sub>12</sub> antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin, Eur Heart J, 27, pp. 1038-1047, (2006)
[2]
van Giezen J.J., Nilsson L., Berntsson P., Wissing B.M., Giordanetto F., Tomlinson W., Et al., Ticagrelor binds to human P2Y<sub>12</sub> independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation, J Thromb Haemostas., 7, pp. 1556-1565, (2009)
[3]
Husted S., Evaluating the risk-benefit profile of the direct-acting P2Y<sub>(12)</sub> inhibitor ticagrelor in acute coronary syndromes, Postgrad Med, 123, pp. 79-90, (2011)
[4]
Wallentin L., Becker R.C., Budaj A., Et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N Engl J Med, 361, pp. 1045-1057, (2009)
[5]
Butler K., Teng R., Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers, Br J Clin Pharmacol, 70, pp. 65-77, (2010)
[6]
Teng R., Butler K., AZD6140, the first reversible oral platelet P2Y<sub>12</sub> receptor antagonist, has linear pharmacokinetics and provides near complete inhibition of platelet aggregation, with reversibility of effect in healthy subjects, Can J Clin Pharmacol., 15, (2010)
[7]
Teng R., Butler K., Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects, Eur J Clin Pharmacol, 66, pp. 487-496, (2010)
[8]
Teng R., Oliver S., Hayes M.A., Butler K., Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects, Drug Metab Dispos, 38, pp. 1514-1521, (2010)
[9]
Zhou D., Andersson T.B., Grimm S.W., In vitro evaluation of potential drug–drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction and differential kinetics, Drug Metab Dispos, 39, pp. 703-710, (2011)
[10]
Gurbel P.A., Bliden K.P., Butler K., Tantry U.S., Gesheff T., Wei C., Et al., Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study, Circulation, 120, pp. 2577-2585, (2009)