Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment.

摘要

Ticagrelor, a P2Y receptor antagonist that inhibits ADP-induced platelet aggregation (IPA), has demonstrated improved outcomes in patients with acute coronary syndromes compared with clopidogrel. Because ticagrelor undergoes extensive hepatic elimination, this study evaluated the effect of mild hepatic impairment on its pharmacokinetics, pharmacodynamics, and safety. A single oral 90-mg ticagrelor dose was administered to volunteers with and without hepatic impairment (10 with Child-Pugh class A; 10 with normal liver function). Absorption of ticagrelor and formation of its active metabolite, AR-C124910XX, were rapid in both groups. Ticagrelor exposure was higher in hepatically impaired volunteers (maximum concentration [C(max)] 12%; area under the plasma concentration-time curve from time 0 to infinity [AUC] 23%) compared with controls. AR-C124910XX exposure was also higher in hepatic impairment (C(max) 17%; AUC 66%). Ticagrelor is highly protein bound (>99.8%); the unbound fraction in plasma was comparable in volunteers with hepatic impairment and controls. Overall, IPA parameters were not significantly different between groups, and similar IPA-concentration profiles were observed. Ticagrelor was well tolerated in both groups, and no adverse events were reported. In conclusion, mild hepatic impairment resulted in modestly higher exposure to ticagrelor and AR-C124910XX, without subsequent effects on pharmacodynamics or tolerability. Based on these data, no ticagrelor dosage adjustment is needed in patients with mild hepatic impairment.