title: Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three- period, cross-over, placebo- and positive-controlled study.
abstract: OBJECTIVE
  Glycopyrronium (NVA237), a once-daily long-acting muscarinic antagonist, has recently been approved for the treatment of patients with chronic obstructive pulmonary disease (COPD). This study evaluated the effect of glycopyrronium on the QT interval and other cardiac parameters in healthy subjects.
  
  
  METHODS
  This randomized, partially blinded, single-dose, placebo- and positive- (moxifloxacin) controlled, three-way cross-over study investigated the effect of a single inhaled supra-therapeutic dose (8-fold clinical dose in COPD patients) of 400 µg glycopyrronium on the Fridericia-corrected QT interval (QTcF; primary objective), Bazettcorrected QT interval (QTcB), heart rate, blood pressure, pharmacokinetics (PK), safety, and tolerability.
  
  
  RESULTS
  A total of 73 healthy male (n = 35) and female (n = 38) subjects, aged between 18 and 45 years, were randomized. Glycopyrronium did not cause significant QTcF prolongation compared to placebo. The largest time-matched mean difference to placebo was 2.97 ms at 5 minutes, with the upper limit of the two-sided 90% confidence interval (CI) being 4.80 ms, excluding a relevant QT effect as defined by the ICH E14 guideline. Glycopyrronium had a slight bradycardic effect with a mean change of -2.88 (90% CI: -3.78, -1.99) beats per minutes (bpm) and a maximum of -5.87 (90% CI: -7.82, -3.92) bpm at 5 hours post-inhalation. No clinically relevant effects were seen on QTcB, other electrocardiogram (ECG) intervals, or blood pressure. Maximum plasma concentration (Cmax) of glycopyrronium was achieved shortly after inhalation (median tmax = 7 minutes). All the treatments were well tolerated with no serious adverse events.
  
  
  CONCLUSIONS
  A supra-therapeutic dose of glycopyrronium had a favorable cardiovascular safety profile with no clinically relevant effect on QT interval.
authors.forename: Anton
authors.initials: A
authors.lastname: Drollmann
authors.forename: Romain
authors.initials: R
authors.lastname: Sechaud
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.forename: Hisanori
authors.initials: H
authors.lastname: Hara
authors.forename: Susan
authors.initials: S
authors.lastname: Uziel-Fusi
authors.forename: Peter
authors.initials: P
authors.lastname: Winkle
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D018592:Cross-Over Studies; D005260:Female; D006024:Glycopyrrolate / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
chemical_list: D018727:Muscarinic Antagonists; D006024:Glycopyrrolate