title: Effect of dual bronchodilation with QVA149 on cardiac safety in healthy volunteers.
abstract: OBJECTIVE
  QVA149 is a dual bronchodilator, containing a fixed-dose combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium, for the treatment of chronic obstructive pulmonary disease (COPD). Here we assess the potential of QVA149 (440/200 μg) at 4-fold the therapeutic dose for causing cardiac pharmacodynamic (PD) effects.
  
  
  METHODS
  This double-blind, randomized study estimated the time-matched largest heart rate (HR) change and average HR change (over 24 hours) from baseline for QVA149 vs. placebo in healthy subjects. Similar analyses were done for QVA149 vs. indacaterol 600 μg, glycopyrronium 200 μg, and salmeterol 200 μg. The time-matched and average change from baseline in QT interval corrected for HR using Fridericia's formula (QTcF), effects on serum potassium and blood glucose, pharmacokinetic (PK) parameters, and safety were also assessed.
  
  
  RESULTS
  Of 50 subjects randomized, 43 completed the study. QVA149, when compared with placebo, showed the time-matched largest mean increase and decrease in HR of 5.69 bpm and -2.51 bpm, respectively, and average HR change from baseline of 0.62 bpm. QVA149 showed no tachycardic potential compared with indacaterol and no relevant tachycardic effect compared with glycopyrronium. No consistent differences were seen in the time-matched largest mean change and average change from baseline in QTcF for QVA149 vs. other treatments. There were no relevant effects of QVA149 on serum potassium and blood glucose. There was no apparent PK/PD relationship between the observed exposures to indacaterol and glycopyrronium in QVA149 on HR and QTcF. There were no deaths or serious adverse events.
  
  
  CONCLUSIONS
  Overall, short-term administration of QVA149 showed a good cardiovascular safety and tolerability profile in healthy subjects.
authors.forename: Anton
authors.initials: A
authors.lastname: Drollmann
authors.forename: Matthew
authors.initials: M
authors.lastname: Brown
authors.forename: Romain
authors.initials: R
authors.lastname: Sechaud
authors.forename: Sheryl
authors.initials: S
authors.lastname: Perry
authors.forename: Hisanori
authors.initials: H
authors.lastname: Hara
authors.forename: Ieuan
authors.initials: I
authors.lastname: Jones
authors.forename: Salvatore
authors.initials: S
authors.lastname: Febbraro
mesh_terms: D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists / Q000009:adverse effects* / Q000493:pharmacokinetics; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006024:Glycopyrrolate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007189:Indans / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics; D061214:Patient Safety; D011188:Potassium / Q000097:blood; D015363:Quinolones / Q000009:adverse effects* / Q000493:pharmacokinetics; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001786:Blood Glucose; D001993:Bronchodilator Agents; D004338:Drug Combinations; D007189:Indans; D018727:Muscarinic Antagonists; D015363:Quinolones; C554862:indacaterol-glycopyrronium combination; D011188:Potassium; D006024:Glycopyrrolate