title: Dabigatran does not prolong the QT interval with supratherapeutic exposure: a thorough QT study in healthy subjects.
abstract: BACKGROUND
  Dabigatran etexilate is a pro-drug of the oral reversible direct thrombin inhibitor dabigatran that interacts with the active site in the catalytic domain of the thrombin molecule.
  
  
  OBJECTIVE
  To assess the electrophysiological effects of therapeutic and supratherapeutic doses of dabigatran etexilate in healthy subjects, a thorough QT study was performed.
  
  
  METHODS
  In this single-centre, blinded, placebo- and active-controlled, four-period, crossover study, 40 healthy Caucasian subjects (20 women and 20 men) received single oral doses of dabigatran etexilate (150 mg and 600 mg), moxifloxacin 400 mg (positive control) or placebo, in a randomized order. Electrocardiogram (ECG) profiles were recorded at baseline and during the randomized study treatment in each period. The individually heart-rate-corrected QT interval (QTcI) was the primary parameter. The primary endpoint was the mean of these QTcI values obtained at 1.5, 2 and 3 h following study drug administration minus the mean of the time-matched QTcI values obtained at baseline day -1. The hypothesis tested was that the difference between each of the two doses of dabigatran etexilate (150 mg and 600 mg) and placebo, for the mean time-matched change from baseline (CfB) of QTcI between 1.5 and 3 h (the primary endpoint), was greater than or equal to 10 ms. Secondary endpoints were the time-matched CfB of QTcI between 0.5 and 24 h post-dose.
  
  
  RESULTS
  All subjects completed the study without premature discontinuation and all treatments were well tolerated. Following dabigatran etexilate administration, the mean values of the placebo-adjusted time-matched CfB of QTcI between 1.5 and 3 h post-dose were close to 0; the upper bound of the two-sided 90 % confidence interval (CI) was 1.4 ms for dabigatran etexilate 150 mg and 1.3 ms for dabigatran etexilate 600 mg. The placebo-adjusted time-matched CfB of QTcI remained close to 0 at all time points, and all 90 % CIs were between -5 ms and 5 ms, well below the pre-defined non-inferiority margin of 10 ms.
  
  
  CONCLUSIONS
  This thorough QT study demonstrated that therapeutic and fourfold supratherapeutic doses of dabigatran etexilate do not prolong QT intervals.
authors.affiliation: Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach/Riss, Germany. arne.ring@uni-ulm.de
authors.forename: Arne
authors.initials: A
authors.lastname: Ring
authors.forename: Karin
authors.initials: K
authors.lastname: Rathgen
authors.forename: Joachim
authors.initials: J
authors.lastname: Stangier
authors.forename: Paul
authors.initials: P
authors.lastname: Reilly
authors.forename: Andreas
authors.initials: A
authors.lastname: Clemens
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Friedman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000991:Antithrombins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D000069604:Dabigatran; D004562:Electrocardiography; D005260:Female; D005858:Germany; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D011725:Pyridines; D000069604:Dabigatran