title: Proarrhythmic safety of repeat doses of mirabegron in healthy subjects: a randomized, double-blind, placebo-, and active-controlled thorough QT study.
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.
authors.affiliation: St Paul's Cardiac Electrophysiology, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Malik
authors.forename: E M
authors.initials: EM
authors.lastname: van Gelderen
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: D L
authors.initials: DL
authors.lastname: Kowalski
authors.forename: M
authors.initials: M
authors.lastname: Yen
authors.forename: R
authors.initials: R
authors.lastname: Goldwater
authors.forename: S K
authors.initials: SK
authors.lastname: Mujais
authors.forename: M P
authors.initials: MP
authors.lastname: Schaddelee
authors.forename: P
authors.initials: P
authors.lastname: de Koning
authors.forename: A
authors.initials: A
authors.lastname: Kaibara
authors.forename: S S
authors.initials: SS
authors.lastname: Moy
authors.forename: J J
authors.initials: JJ
authors.lastname: Keirns
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000009:adverse effects / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics; D012727:Sex Characteristics; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D053201:Urinary Bladder, Overactive / Q000188:drug therapy; D055815:Young Adult
chemical_list: D000083:Acetanilides; D000318:Adrenergic beta-Agonists; D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D013844:Thiazoles; C520025:mirabegron; D000077266:Moxifloxacin