title: Single-dose ticagrelor does not prolong the QT interval in healthy subjects.
abstract: Ticagrelor (AZD6140), the first reversibly binding oral platelet P2Y12 receptor inhibitor, is currently under development for reduction of thrombotic events in patients with acute coronary syndrome (ACS).
  
  
  OBJECTIVE
  This study was designed to assess the potential effects of a single oral dose of ticagrelor on QT interval.
  
  
  METHODS
  In this randomized, double-blind, double-dummy, placebo- and positive-controlled, three-way crossover study, 36 healthy males received single doses of ticagrelor 900 mg, moxifloxacin (positive control) 400 mg, or placebo in three treatment periods. This ticagrelor dose is substantially higher than the proposed therapeutic dose (90 mg twice daily after a 180 mg loading dose). QT intervals were assessed from 12-lead digital electrocardiogram (ECG) recordings over 24 h. Plasma levels of ticagrelor and its major metabolite AR-C124910XX were measured. Exploratory analyses of exposure-QTc interval relationships were conducted. Safety assessments were made throughout the study.
  
  
  RESULTS
  Mean QTcX, QTcF, and QTcB intervals were similar between ticagrelor and placebo. All point estimates for comparisons between ticagrelor and placebo in QTcX over 24 h post dosing were < 5 milliseconds and all upper confidence limits (UCL) from two-sided 95% confidence intervals were < 10 milliseconds (maximum time-matched mean effect 2.27 milliseconds with UCL 6.05 milliseconds at 12 h). With moxifloxacin, all point estimates and UCLs (except at 24 h post dose) were > 5 milliseconds and > 10 milliseconds, respectively, versus placebo; indicating the study had sufficient sensitivity to detect clinically meaningful changes in QT interval. There was no apparent relationship between ticagrelor or AR-C124910XX levels and QT intervals. Ticagrelor was well tolerated at the tested dose.
  
  
  CONCLUSIONS
  A single oral dose of 900 mg ticagrelor did not prolong the QT interval in healthy volunteers compared with placebo. Thus, it is expected that ticagrelor will not affect cardiac repolarization in ACS patients.
authors.affiliation: AstraZeneca LP, Wilmington, DE, USA.
authors.forename: K
authors.initials: K
authors.lastname: Butler
authors.forename: C
authors.initials: C
authors.lastname: Wei
authors.forename: R
authors.initials: R
authors.lastname: Teng
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D006801:Humans; D008297:Male; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077486:Ticagrelor
chemical_list: C548576:P2RY12 protein, human; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077486:Ticagrelor; D000241:Adenosine