Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers

center dot The antiplatelet agent clopidogrel is currently the recommended treatment for acute coronary syndrome (ACS). center dot Inhibition of platelet aggregation (IPA) with clopidogrel is insufficient, which increases the risk for recurrent ischaemic events. Therefore, there is a need for antiplatelet agents with improved IPA. center dot Ticagrelor (AZD6140) is a new antiplatelet agent in clinical development for reduction of thrombotic events in patients with ACS. WHAT THIS STUDY ADDS center dot This study assesses the optimal dosing schedule for ticagrelor in healthy volunteers and compares the degree of IPA with clopidogrel. center dot Our findings illustrate that the pharmacokinetics of ticagrelor are predictable and are associated with consistent inhibition of platelet activity. center dot IPA with ticagrelor was greater and better sustained at high levels with twice daily ticagrelor than once daily regimens. AIM To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y(12) receptor antagonist, in healthy volunteers. METHODS This was a randomized, single-blind, placebo-controlled, ascending dose study. Thirty-two subjects received ticagrelor 50-600 mg once daily or 50-300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day-1, or placebo for 14 days. RESULTS Ticagrelor was absorbed with median t(max) 1.5-3 h, exhibiting predictable pharmacokinetics over the 50-600 mg dose range. Mean C(max) and AUC for ticagrelor and its main metabolite, AR-C124910XX, increased approximately dose-proportionately (approximately 2.2- to 2.4-fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses >= 300 mg once daily and >= 100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor >= 100 mg twice daily was greater and less variable (93-100%, range 65-100%) than with clopidogrel (77%, range 11-100%) at trough concentrations. No safety or tolerability issues were identified. CONCLUSIONS Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50-600 mg once daily and 50-300 mg twice daily with C(max) and AUC(0,t) increasing approximately dose-proportionally. Greater and more consistent IPA with ticagrelor at doses >= 100 mg twice daily and >= 300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day-1 was well tolerated.