title: Randomized, blinded, placebo- and positive-controlled crossover study to determine the effect of multiple doses of apixaban on the QTc interval.
abstract: Apixaban is an oral, direct factor Xa inhibitor indicated for the prevention and treatment of thromboembolic disease. This randomized, blinded, 4-way crossover study investigated the potential effect of apixaban on the QTc interval. Forty healthy subjects (39 completers) each received 3 days of the following treatments: blinded apixaban 10 mg once daily (QD), 50 mg QD (supratherapeutic), matched apixaban placebo QD, and a single dose of open-label moxifloxacin 400 mg on Day 3, preceded by 2 days of placebo QD. Triplicate electrocardiograms obtained over 24 hours on Days -1 (baseline) and 3 were read by a blinded third party. The mean placebo-adjusted, time-matched, Fridericia-corrected change from baseline QTc (ΔΔQTcF) for apixaban and moxifloxacin was estimated at each time point. The maximum ΔΔQTcF was 1.51 milliseconds (one-sided upper 95% confidence interval [CI] 3.71 milliseconds) after apixaban 50 mg QD, 1.36 milliseconds (one-sided upper 95%CI 3.54 milliseconds) after apixaban 10 mg QD, and 10.21 milliseconds (lower 95%CI 8.07 milliseconds) after moxifloxacin. Concentration-response analysis suggested no evidence of a positive relationship between apixaban concentration and ΔQTcF. Apixaban doses up to 50 mg QD for 3 days were well tolerated and did not prolong the QTc interval in healthy subjects.
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Frost
authors.forename: Sunil
authors.initials: S
authors.lastname: Nepal
authors.forename: Wonkyung
authors.initials: W
authors.lastname: Byon
authors.forename: Kenneth
authors.initials: K
authors.lastname: Moore
authors.forename: Richard A
authors.initials: RA
authors.lastname: Reeves
authors.forename: Rebecca
authors.initials: R
authors.lastname: Boyd
authors.forename: Frank
authors.initials: F
authors.lastname: LaCreta
mesh_terms: D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D065427:Factor Xa Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D006801:Humans; D008297:Male; D000077266:Moxifloxacin; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D011728:Pyridones / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D065427:Factor Xa Inhibitors; D024841:Fluoroquinolones; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D000077266:Moxifloxacin
keywords: anticoagulation; apixaban; thorough QT study