title: Safety, tolerability, pharmacokinetics and pharmacodynamics of high single-ascending doses of ticagrelor in healthy volunteers.
abstract: OBJECTIVE
  Previous studies have indicated that ticagrelor is well tolerated and exhibits linear pharmacokinetics up to doses of 600 mg/day. The safety, tolerability, pharmacokinetics and pharmacodynamics (bleeding times and pulmonary function tests) of high single-ascending doses of ticagrelor were assessed to determine the maximum tolerated dose of ticagrelor.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled study. Eight healthy volunteers were planned for enrollment in each of 3 dose groups, ticagrelor 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.
  
  
  CONCLUSIONS
  These results indicate that the maximum tolerated single dose of ticagrelor is 900 mg in healthy volunteers.
authors.forename: Renli
authors.initials: R
authors.lastname: Teng
authors.forename: Kathleen
authors.initials: K
authors.lastname: Butler
mesh_terms: D000042:Absorption; D000241:Adenosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D019540:Area Under Curve; D001760:Bleeding Time; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D000077486:Ticagrelor; D055815:Young Adult
chemical_list: D000077486:Ticagrelor; D000241:Adenosine