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

Abstract

AIMThe aim of the study was to assess ticagrelor's effects on inhibition of platelet aggregation (IPA), P2Y 12 reaction units (PRU, measure of platelet P2Y 12 receptor blockade), pharmacokinetic (PK) parameters and safety in Chinese patients with stable coronary artery disease (CAD). METHODSThis was an open label, single centre, randomized study. Thirty-six patients on low dose aspirin (75-100 mg day -1 ) received ticagrelor 45, 60 or 90 mg (single dose, days 1 and 7; twice daily, days 3-6). IPA (final extent), PRU and ticagrelor and AR-C124910XX plasma concentrations were determined. RESULTSOn day 1, peak IPA >80% occurred 2-6 h post-dose (all doses). PRU was markedly reduced at 1 h vs. baseline (all doses). With ticagrelor 45 and 90 mg twice daily, maximum IPA (mean, SD) was 91% (13%), and 99% (3%), and maximum PRU reduction from baseline (mean, SD) was 82% (17%) and 92% (9%) CONCLUSIONSIn Chinese patients with CAD, ticagrelor (45, 60 and 90 mg) markedly reduced platelet aggregation. The IPA and PRU magnitude increased generally with increasing doses. However, the mean pharmacodynamic differences between 45 and 60 mg doses were small. Following single and multiple doses, the mean C max and AUC values of ticagrelor and AR-C124910XX increased approximately dose proportionally between 45 and 90 mg doses. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Ticagrelor (an oral, direct acting, reversibly binding P2Y 12 receptor antagonist) is approved for preventing atherothrombotic events in patients with acute coronary syndromes.• Ticagrelor bioavailability is~40% higher in Asians than Caucasians.• Pharmacodynamics, pharmacokinetics and safety of ticagrelor have not been evaluated previously in Chinese patients with stable coronary artery disease. WHAT THIS STUDY ADDS• In Chinese patients with coronary artery disease, ticagrelor (45, 60 or 90 mg twice daily) markedly inhibited platelet aggregation.• Dose-related changes in pharmacodynamic/pharmacokinetic parameters occurred with ticagrelor.• Ticagrelor exposure was consistent with previous Asian studies and higher than in Caucasian studies.

Pharmacokinetic Profiles of Ticagrelor Orodispersible Tablets in Healthy Western and Japanese Subjects

“…With regards to safety and tolerability, a single, 90-mg dose of ticagrelor was well tolerated in both studies. Moreover, the AE profile of ticagrelor in the present studies was consistent with previous studies in Caucasian subjects [ 5 , 12 , 13 , 17 ], and Asian subjects [ 18 – 21 ]. No new safety concerns with ticagrelor were identified with the OD tablet versus the IR tablet.…”

“…In the present Western study, the ticagrelor and AR-C124910XX pharmacokinetic parameters are generally comparable to previous studies in Caucasian subjects with a single 90-mg ticagrelor dose [ 12 , 13 ]. Furthermore, the pharmacokinetic parameters in the current Japanese study are also generally similar to previous studies in Asian subjects, including Chinese [ 18 ] and Japanese [ 19 ] healthy subjects and in Japanese, Asian [ 20 ], and Chinese patients with coronary artery disease [ 21 ]. With regards to safety and tolerability, a single, 90-mg dose of ticagrelor was well tolerated in both studies.…”

“…The main pharmacodynamic effect, platelet inhibition, is rapid, temporary, and related to plasma concentrations of both ticagrelor and AR-C124910XX [ 3 , 12 , 13 , 16 , 17 ]. In Asian subjects, mean bioavailability of ticagrelor and AR-C124910XX is ~40% higher versus Caucasian subjects [ 18 – 21 ]. However, in the Asia ( n = 1056) and China ( n = 383) subgroups of the PLATO study, the efficacy and safety of ticagrelor versus clopidogrel were generally consistent with the overall study population [ 5 ].…”

Evaluation of pharmacokinetic, pharmacodynamic, efficacy, and safety data of low-dose ticagrelor versus standard dose in East Asians: a systematic review

“…Seven studies were included in this systematic review, which included healthy subjects, 19 , 20 patients with ACS, 21 , 22 patients 1–3 years post-MI, 1 and those with stable coronary artery disease. 23 , 24 Most of the studies included the half dose of ticagrelor as the low dose (90 mg LD or 45 mg BID MD), although one study also included the 60 mg BID dose of ticagrelor. 24 Of the seven included studies, six studies were conducted in Asia and one study was conducted worldwide including 11.0% of Asians.…”

“… 23 , 24 Most of the studies included the half dose of ticagrelor as the low dose (90 mg LD or 45 mg BID MD), although one study also included the 60 mg BID dose of ticagrelor. 24 Of the seven included studies, six studies were conducted in Asia and one study was conducted worldwide including 11.0% of Asians. 1 One article in Chinese was translated into English for analysis.…”