Abstract 5494: Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients With Stable Coronary Artery Disease
Background: Ticagrelor (T), the first reversibly binding oral P2Y12 receptor antagonist, has been evaluated in patients with ACS. Reversible inhibition is desirable for patients who experience bleeding complications or require invasive procedures.
Methods: Two studies examined the pharmacokinetics (PK) of T in patients with stable coronary artery disease (CAD). In the multicenter, randomized, double-blind parallel group ONSET-OFFSET study, patients with stable CAD currently receiving aspirin (75–100 mg) were randomized to doses of T (180 mg load, 90 mg bid maintenance [n=57]), clopidogrel (C) (600 mg load, 75 mg qd maintenance [n=54]) or placebo (n=12) for 6 weeks. PK of T and AR-C124910XX (AR), an active metabolite, were evaluated following loading and last maintenance doses. In RESPOND (2-way crossover design), patients with stable CAD classified as C non-responders (n=41) and responders (n=57) were randomized to 14 days treatment with C 600 mg load/75 mg qd or T 180 mg loading/90 mg bid with no washout between treatments. On Days 1 and 14, tmax, Cmax and AUC0 – 8of T and AR were evaluated.
Results: In ONSET-OFFSET, Cmax, tmax and t1/2 values of T (733 ng/mL, 2 h, and 10.2 h, respectively) and AR (210.3 ng/mL, 2.1 h, and 12.8 h) at 90 mg bid were comparable to those seen previously in healthy subjects. Emax estimates of final extent IPA (%) vs plasma concentration curves of T and AR were 98.6% and 91.8%, respectively. Trough plasma T (304.6 ng/mL) and AR (120.7 ng/mL) concentrations were 4 and 6 times higher than the respective EC50 estimates (58.6 ng/mL and 15.7 ng/mL, respectively). In RESPOND, mean Cmax and AUC0 – 8 of T following 2-week maintenance doses were similar between C responders (724.2 ng/mL and 3982.7 ng·h/mL) and non-responders (764.4 ng/mL and 3985.2 ng·h/mL). PK of T were not affected when T was administered 24 h post C dosing.
Conclusions: This dosing regimen of T and AR effectively inhibited platelet aggregation; trough plasma levels of T (90 mg bid) and AR were sufficient to achieve high IPA. The pharmacodynamic response followed PK. Importantly, PK of T administered after crossover from C were unchanged and not affected by patient responsiveness to C.