Safety, tolerability, pharmacokinetics and pharmacodynamics of high single-ascending doses of ticagrelor in healthy volunteers

摘要

Objective: Previous studies have indicated that ticagrelor is well tolerated and exhibits linear pharmacokinetics up to doses of 600 mg/day. The safety, tol-erability, pharmacokinetics and pharmaco-dynamics (bleeding times and pulmonary function tests) of high single-ascending doses of ticagrelor were assessed to determine the maximum tolerated dose of ticagrelor. Materials and methods: This was a randomized, double-blind, placebo-controlled study. Eight healthy volunteers were planned for enrollment in each of 3 dose groups, ticagre-lor 900 mg, 1, 260 mg, and 1, 620 mg (6: 2 ratio ticagrelor: placebo). Results: The study stopping criteria were met when 3 of the 6 volunteers receiving ticagrelor 1, 260 mg experienced moderate gastrointestinal adverse events (AE); none were observed with placebo. One volunteer receiving ticagrelor 1, 260 mg had a serious AE - sinus arrest, high-grade atrioventricular block, and ventricular escape rhythm with syncope - and another volunteer had brief, mild dyspnea. Ticagrelor 900 mg was well tolerated. Total exposure to ticagrelor increased dose proportionally. Peak plasma concentration (Cmax) for ticagrelor did not increase much, most likely due to delayed absorption. There were no relevant changes in respiratory parameters. Bleeding times were prolonged in those receiving ticagrelor with respect to placebo, with longer bleeding times in volunteers receiving ticagrelor 1, 260 mg than in volunteers receiving 900 mg; no bleeding events were reported. Conclusion: These results indicate that the maximum tolerated single dose of ticagrelor is 900 mg in healthy volunteers.