Supra-therapeutic doses of roflumilast have no effect on cardiac repolarization in healthy subjects

Abstract

Objective: This study assesses the potential of the phosphodiesterase 4 inhibitor roflumilast to affect cardiac repolarization.Methods: In this randomized, placebo-controlled study (n = 80), 40 healthy subjects received moxifloxacin 400 mg p.o. (positive control for prolongation of QT/heart-rate corrected QT [QTc]) and another 40 received placebo. After a 1-day washout, subjects received placebo or ascending doses of roflumilast 500 (therapeutic dose), 750 or 1000 μg/day p.o., for 14, 7 and 14 days, respectively. QT intervals were measured and corrected for heart rate with a Fridericia algorithm (QTcF). The primary endpoint was the largest mean time-matched change in QTcF from baseline (day 1). Safety and tolerability were monitored.Results: Moxifloxacin gave a maximum time-matched change in QTcF versus baseline of 6.79 ms. Repeated administration of roflumilast 500 and 1000 μg resulted in maximum QTcF changes from baseline of -3.23 and -4.81 ms, respectively, confirming the absence of any QT/QTc prolongation at therapeutic and supra-therapeutic dosing. There were no changes in other electrocardiographic variables or time intervals, and roflumilast was well tolerated.Conclusions: Repeated administration of roflumilast at doses ≤ 1000 μg/day had no effect on cardiac repolarization or overall cardiac safety evaluations in healthy subjects.Clinical trial registration number: ISRCTN63818313