Randomized, double-blind, crossover study to investigate the effect of rivaroxaban on QT-interval prolongation.
BACKGROUND
Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Unwanted pro-arrhythmic effects are a common reason for drugs failing to gain regulatory approval; these properties can be detected by assessing the effect of the drug on the QT interval.


OBJECTIVE
This study was performed, in accordance with International Conference on Harmonisation (ICH) E14 guidance, to assess whether rivaroxaban prolongs the QT interval.


METHODS
This was a prospective, randomized, double-blind, double-dummy, four-way crossover study.


METHODS
The study was conducted at a clinical pharmacology research unit.


METHODS
Healthy male and female subjects (n = 54) aged > or =50 years were enrolled and remained in the study unit for 3 days for each treatment. Of these, 50 patients were eligible for the QT analysis.


METHODS
Subjects received single oral doses of rivaroxaban 45 mg or 15 mg, moxifloxacin 400 mg (positive control), or placebo.


METHODS
Multiple ECGs were taken at frequent intervals after drug administration, and the QT interval was measured manually under blinded conditions at a central laboratory. The Fridericia correction formula (QTcF) was used to correct the QT interval for heart rate. The primary outcome was the effect of rivaroxaban or moxifloxacin on the placebo-subtracted QTcF 3 hours after administration. The frequency of outlying QTcF values and the tolerability of the treatments were also assessed.


RESULTS
All treatments were well tolerated and had no effect on heart rate. Moxifloxacin established the required assay sensitivity; placebo-subtracted QTcF 3 hours after moxifloxacin administration was prolonged by 9.77 ms (95% CI 7.39, 12.15). Placebo-subtracted QTcF values 3 hours after rivaroxaban administration were -0.91 ms (95% CI -3.33, 1.52) and -1.83 ms (95% CI -4.19, 0.54) with rivaroxaban 45 mg and 15 mg, respectively. QTcF was not prolonged with rivaroxaban at any time, and the frequency of outlying results with rivaroxaban and placebo was similar.


CONCLUSIONS
This thorough QT study, which was performed in accordance with ICH E14 guidelines, shows that rivaroxaban does not prolong the QTc interval. Therefore, the potential of rivaroxaban for the prevention and treatment of thromboembolic disorders, including chronic cardiovascular disorders, can be investigated in appropriate clinical studies without the need for intensive monitoring of the QTc interval.
Kubitza
Dagmar
D
Clinical Pharmacology, Pharmacometry, Bayer HealthCare AG, Wuppertal, Germany. dagmar.kubitza@bayerhealthcare.com
Mueck
Wolfgang
W
Becka
Michael
M
D000284:Administration, Oral; D000368:Aged; D000465:Algorithms; D000990:Antithrombin III / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001372:Aza Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects* / Q000706:statistics & numerical data; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077266:Moxifloxacin; D011446:Prospective Studies; D011804:Quinolines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000069552:Rivaroxaban; D012737:Sex Factors; D013876:Thiophenes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors
D001372:Aza Compounds; D024841:Fluoroquinolones; D009025:Morpholines; D011804:Quinolines; D013876:Thiophenes; D000990:Antithrombin III; D000069552:Rivaroxaban; D000077266:Moxifloxacin