E doxaban (the free base of DU-176b), an orally active direct inhibitor of Factor Xa, 1,2 is a novel antithrombotic agent that is under development for the prevention of stroke in patients with atrial fibrillation. Edoxaban has linear pharmacokinetics, with rapid absorption observed between 1 and 3 hours postdose followed by biphasic disposition with terminal elimination half-life of approximately 8 to 10 hours. 3 The International Conference on Harmonisation (ICH) E14 Guideline requires that all new drug applications submitted for drugs that have systemic bioavailability include a "thorough QT/QTc" study. 4 This now termed is "thorough ECG trial" since all electrocardiogram (ECG) parameters are scrutinized in the study. 5 This ICH requirement evolved from an appreciation that some noncardiac drugs had the ability to delay ventricular repolarization, which has been associated with cardiac arrhythmias, particularly torsades de pointes. The designs of thorough ECG studies to accurately measure the effect of a new drug on the ECG with a special focus on the QTc interval are well described in the E14 guideline and were recently reviewed by Morganroth. 5 The current study was a thorough ECG study to further characterize the effect of edoxaban on the ECG with a special focus on the QTc interval. The highest dose administered in the phase III study is 60 mg daily (ENGAGE AF-TIMI 48). 6 The single 90-mg dose would provide similar or greater exposure than the daily 60-mg dose at steady state. The 180-mg dose was considered the supratherapeutic dose, 3 and 5 times the proposed therapeutic doses of 60 mg and 30 mg, respectively. Since the highest previously administered doses of 120 mg and 150 mg in the single ascending dose study were associated with elevated bleeding times, it was felt that 180 mg was the highest single dose that we could safely administer, posing minimal bleeding risk, to healthy volunteers. 3 In addition, the dose regimen of 60 mg twice a day was prematurely discontinued in the phase II study of subjects with atrial fibrillation because of increased bleeding relative to warfarin 7 . The positive control was moxifloxacin (Avelox) 400 mg 8 , and the negative control was a placebo treatment. MEthods study designThis was a single-dose, randomized, 4-period crossover study of blinded edoxaban (90 mg and 180 mg), matching placebo, and open-label moxifloxacin (Avelox) 400 mg. A total of 64 subjects were enrolled to complete at least 52 subjects based on sample size with 90% power. Study subjects were healthy men and women aged 18 to 45 years, with a body mass index (BMI) between 19 and 31 kg/m 2 , no history of a bleeding diathesis, and a negative fecal blood test at study entry. All subjects provided written informed consent prior to screening and were screened by physical examination, medical history, clinical laboratory data, and ECG. They were admitted on day -2 and discharged on day 3 for a total of 5 days for each of the 4 periods. To ensure continued eligibility, at check-in for each treatment period su...
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