title: Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment.
abstract: Ticagrelor, a P2Y(12) receptor antagonist, is approved in the European Union and the US for the prevention of thrombotic events in patients with acute coronary syndromes. Renal dysfunction potentially affects drug disposition. Ticagrelor pharmacokinetics, pharmacodynamics, and safety in renal impairment were assessed. A single 180-mg ticagrelor dose was administered to volunteers with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) and normal renal function (CrCL ≥ 80 mL/min; n = 10/group). Severe renal impairment did not significantly affect ticagrelor's pharmacokinetics, pharmacodynamics, or safety. Ticagrelor absorption and AR-C124910XX (active metabolite) formation were rapid. In renally impaired volunteers, ticagrelor mean maximum concentration (C(max)) and area under the plasma concentration-time curve from zero to infinity were 20% lower and for AR-C124910XX was 17% higher versus normal volunteers. Ticagrelor systemic exposure was low in 3 volunteers (CrCL < 20 mL/min), but data were variable. Onset and offset of final-extent inhibition of platelet aggregation were comparable in both groups. Inhibition of platelet aggregation parameters and profiles were similar between groups, indicating that platelet sensitivity to ticagrelor was not affected by severe renal impairment. Ticagrelor was well tolerated in both groups with few adverse events. No ticagrelor dose adjustment is required for renally impaired patients.
authors.affiliation: AstraZeneca LP, Wilmington, Delaware 19850-5437, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Butler
authors.forename: Renli
authors.initials: R
authors.lastname: Teng
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051437:Renal Insufficiency / Q000378:metabolism* / Q000503:physiopathology; D000077486:Ticagrelor
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000077486:Ticagrelor; D000241:Adenosine