Testing single dose moxifloxacin and ibutilide as positive controls for detecting QTC prolongation in healthy subjects

Abstract

The ability to detect drug-induced changes in the QTc interval has become critical in drug development. Inclusion of a positive control can assure a study's ability to detect this effect. At weekly intervals, in a single blind randomized, crossover study, we administered either moxifloxacin 400 mg orally, ibutilide 0.002 mg/kg IV over 10 min, or placebo (infusion and tablets) to 23 healthy male and female subjects. Thirty-eight 12-lead ECGs were obtained on each treatment day. Subjects tolerated the treatments well and no clinically significant arrhythmias were detected on telemetry. Initial data analysis has focused on the machine-measured QT intervals with the Fridericia correction for heart rate. Using a time-matched analysis, the mean QTc change (95% CI) 4-11 hours after the moxifloxacin dose was 5.9 msec (2.0, 9.8). The QTc interval was elevated from 7–30 min after the start of the ibutilide infusion with a mean QTc change (95% CI) of 11.3 msec (3.9, 18.7). Cardiac intervals were also hand-measured by a cardiologist, and these values will be compared to the machine-measured values. Our preliminary data analysis shows that single-dose active controls (ibutilide or moxifloxacin) are not associated with a substantial proarrhythmic risk (< 20 msec) and produce detectable (> 5 msec) prolongation of the QTc interval. Clinical Pharmacology & Therapeutics (2004) 75, P47–P47; doi: 10.1016/j.clpt.2003.11.177