Pharmacodynamics, pharmacokinetics and safety of ticagrelor in Asian patients with stable coronary artery disease
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.
KeywordsTicagrelor Pharmacokinetics Pharmacodynamics P2Y12 receptor antagonist Japanese
Medical writing support was provided by Rick Flemming and David Evans at Gardiner Caldwell Communications and was funded by AstraZeneca. The authors acknowledge Takaaki Isshiki (Teikyo University School of Medicine), Hiroyuki Daida (Juntendo University Faculty of Medicine), Yasuo Ikeda (Waseda University School of Advanced Science and Engineering), Hisao Ogawa (Kumamoto University School of Medicine) and Makoto Takagi (Saiseikai Central Hospital), who were members of the data safety monitoring board. Technical training in the use of platelet aggregation equipment and the surveillance of aggregation curve accuracy was provided to staff from all sites by Laura West of the University of Sheffield. The authors would also like to thank all medical staff and patients involved in the study.
- 1.Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27:1038–47.PubMedCrossRefGoogle Scholar
- 6.Teng R, Butler K. AZD6140, the first reversible oral platelet P2Y12 receptor antagonist, has linear pharmacokinetics and provides near complete inhibition of platelet aggregation, with reversibility of effect in healthy subjects. Can J Clin Pharmacol. 2010;15:e426.Google Scholar
- 10.Gurbel PA, Bliden KP, Butler K, Tantry US, 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. 2009;120:2577–85.PubMedCrossRefGoogle Scholar
- 15.Teng R, Butler K. Comparison of the pharmacokinetics, pharmacodynamics and tolerability of single and multiple doses of ticagrelor in healthy Japanese and Caucasian volunteers. Int J Clin Pharmacol Ther. 2013 [Epub ahead of print].Google Scholar
- 18.James S, Åkerblom A, Cannon CP, Emanuelsson H, Husted S, Katus H, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet Inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605.PubMedCrossRefGoogle Scholar
- 22.Li H, Butler K, Yang L, Yang Z, Teng R. Pharmacokinetics and tolerability of single- and multiple-doses of ticagrelor in healthy Chinese volunteers. Clin Drug Investig. 2012;32:87–97.Google Scholar