Evaluation of the pharmacokinetics and pharmacodynamics of ticagrelor co-administered with aspirin in healthy volunteers

Abstract

The results of two independent, randomized, two-period crossover, single-center studies, conducted to assess the pharmacokinetics of ticagrelor ± aspirin, inhibition of platelet aggregation (IPA) with ticagrelor/aspirin vs. clopidogrel/aspirin, and safety, tolerability, and bleeding times are reported here. In Study A (open-label), 16 volunteers received ticagrelor (50 mg bid Days 1-5; 200 mg bid Days 6-9; one 200 mg dose on Day 10) ± 300 mg qd aspirin (Days 1-10). In Study B (double-blind, double-dummy), 16 volunteers received aspirin (300 mg loading dose/75 mg qd Days 2-9) with either ticagrelor (200 mg bid Days 4-8, one 200 mg dose on Day 9) or clopidogrel (300 mg loading dose Day 4, 75 mg qd Days 5-9). At steady-state ticagrelor (50 mg bid, or 200 mg bid), concomitant aspirin (300 mg qd) had no effect on mean maximum plasma concentration (Cmax), median time to Cmax (tmax), or mean area under the plasma concentration-time curve for the dosing interval (AUC0-τ) for ticagrelor and its primary metabolite, AR-C124910XX. Following 200 mg bid ticagrelor, mean Cmax and AUC0-τ for both parent and metabolite were comparable with co-administration of aspirin at 75 mg and 300 mg qd. Aspirin (300 mg qd) had no effect on IPA (ADP-induced) by ticagrelor. However, aspirin and ticagrelor had an additive effect on IPA (collagen-induced). Ticagrelor/aspirin increased bleeding times vs. baseline. Ticagrelor/aspirin co-administration was well tolerated at all dose combinations evaluated. In summary, the findings of this study demonstrate that co-administration of aspirin (300 mg qd) with ticagrelor (50 mg bid, or 200 mg bid) had no effect on ticagrelor pharmacokinetics or IPA (ADP-induced) by ticagrelor.

Figures

Figure 1.

Designs for Study A and Study B.

Figure 2.

Plasma concentration profiles of (a) ticagrelor and (b) AR-C124910XX following administration of ticagrelor (50 mg bid for 5 days, or 200 mg bid for 4 days then qd for 1 day) ± once-daily aspirin (300 mg) (Study A). Values are mean ± SD, n = 13 at each time point.

Figure 3.

Inhibition of platelet aggregation (final-extent, 20 µM ADP-induced) following administration of ticagrelor (a) 50 mg bid for 5 days, and (b) 200 mg bid for 4 days then qd for 1 day, ± once-daily aspirin (300 mg) (Study A). Values are mean ± SD, n = 11 or 12 at each time point.

Figure 4.

Inhibition of platelet aggregation (final-extent, 20 µM ADP-induced) following administration of ticagrelor (200 mg bid for 5 days then a single 200 mg dose for 1 day) + aspirin (75 mg qd) and clopidogrel (loading dose 300 mg on Day 1 then 75 mg qd for 5 days) + aspirin (75 mg qd) (Study B). Values are mean ± SD, n = 16 at each time point.

Figure 5.

Inhibition of platelet aggregation (final-extent, collagen-induced) following the administration of (a) ticagrelor at 50 mg bid for 5 days, and 200 mg bid for 4 days then qd for 1 day, ± once-daily aspirin (300 mg) (Study A), and (b) ticagrelor (200 mg bid for 5 days then a single 200 mg dose for 1 day) + aspirin (75 mg qd) and clopidogrel (loading dose 300 mg on Day 1 then 75 mg qd for 5 days) + aspirin (75 mg qd) (Study B). Values are mean ± SD.