Proarrhythmic safety of repeat doses of mirabegron in healthy subjects: a randomized, double-blind, placebo-, and active-controlled thorough QT study

Clin Pharmacol Ther. 2012 Dec;92(6):696-706. doi: 10.1038/clpt.2012.181. Epub 2012 Nov 14.

Abstract

Potential effects of the selective β(3)-adrenoceptor agonist mirabegron on cardiac repolarization were studied in healthy subjects. The four-arm, parallel, two-way crossover study was double-blind and placebo- and active (moxifloxacin)-controlled. After 2 baseline ECG days, subjects were randomized to one of eight treatment sequences (22 females and 22 males per sequence) of placebo crossed over with once-daily (10 days) 50, 100, or 200 mg mirabegron or a single 400-mg moxifloxacin dose on day 10. In each period, continuous ECGs were recorded at two baselines and on the last drug administration day. The lower one-sided 95% confidence interval for moxifloxacin effect on QTcI was >5 ms, demonstrating assay sensitivity. According to ICH E14 criteria, mirabegron did not cause QTcI prolongation at the 50-mg therapeutic and 100-mg supratherapeutic doses in either sex. Mirabegron prolonged QTcI interval at the 200-mg supratherapeutic dose (upper one-sided 95% CI >10 ms) in females, but not in males.

Trial registration: ClinicalTrials.gov NCT01199523.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Acetanilides / administration & dosage
  • Acetanilides / adverse effects*
  • Acetanilides / therapeutic use
  • Adolescent
  • Adrenergic beta-Agonists / administration & dosage
  • Adrenergic beta-Agonists / adverse effects*
  • Adrenergic beta-Agonists / therapeutic use
  • Adult
  • Anti-Infective Agents / adverse effects
  • Anti-Infective Agents / pharmacokinetics
  • Aza Compounds / adverse effects
  • Aza Compounds / pharmacokinetics
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Electrocardiography / drug effects*
  • Female
  • Fluoroquinolones
  • Heart Rate / drug effects
  • Humans
  • Long QT Syndrome / chemically induced*
  • Long QT Syndrome / epidemiology
  • Male
  • Middle Aged
  • Moxifloxacin
  • Quinolines / adverse effects
  • Quinolines / pharmacokinetics
  • Sex Characteristics
  • Thiazoles / administration & dosage
  • Thiazoles / adverse effects*
  • Thiazoles / therapeutic use
  • Urinary Bladder, Overactive / drug therapy
  • Young Adult

Substances

  • Acetanilides
  • Adrenergic beta-Agonists
  • Anti-Infective Agents
  • Aza Compounds
  • Fluoroquinolones
  • Quinolines
  • Thiazoles
  • mirabegron
  • Moxifloxacin

Associated data

  • ClinicalTrials.gov/NCT01199523