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

• Published in: Clinical pharmacology and therapeutics Vol. 92; no. 6; p. 696
• Main Authors: Malik, M, van Gelderen, E M, Lee, J H, Kowalski, D L, Yen, M, Goldwater, R, Mujais, S K, Schaddelee, M P, de Koning, P, Kaibara, A, Moy, S S, Keirns, J J
• Format: Journal Article
• Language: English
• Published: United States 01.12.2012
• Subjects: 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; Quinolines - adverse effects; Quinolines - pharmacokinetics; Sex Characteristics; Thiazoles - administration & dosage; Thiazoles - adverse effects; Thiazoles - therapeutic use; Urinary Bladder, Overactive - drug therapy; Young Adult
• ISSN: 1532-6535
• DOI: 10.1038/clpt.2012.181

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.