title: 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 (QTc(F)). The primary endpoint was the largest mean time-matched change in QTc(F) from baseline (day 1). Safety and tolerability were monitored.
  
  
  RESULTS
  Moxifloxacin gave a maximum time-matched change in QTc(F) versus baseline of 6.79 ms. Repeated administration of roflumilast 500 and 1000 μg resulted in maximum QTc(F) 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.
  
  
  BACKGROUND
  ISRCTN63818313
authors.affiliation: Nycomed GmbH, Department of Pharmacometrics and Pharmacokinetics , Byk-Gulden-Str. 2, 78467 Konstanz , Germany. andreas.huennemeyer@nycomed.com
authors.forename: Andreas
authors.initials: A
authors.lastname: Huennemeyer
authors.forename: Nassr
authors.initials: N
authors.lastname: Nassr
authors.forename: Dirk
authors.initials: D
authors.lastname: Bredenbröker
authors.forename: Gezim
authors.initials: G
authors.lastname: Lahu
mesh_terms: D000293:Adolescent; D000328:Adult; D000631:Aminopyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001549:Benzamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003521:Cyclopropanes / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects* / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; C424423:Roflumilast