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; pp. 696 - 706
• 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: Basingstoke Blackwell Publishing Ltd 01-12-2012; Nature Publishing Group
• 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; Biological and medical sciences; 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; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Quinolines - adverse effects; Quinolines - pharmacokinetics; Sex Characteristics; Thiazoles - administration & dosage; Thiazoles - adverse effects; Thiazoles - therapeutic use; Urinary Bladder, Overactive - drug therapy; Young Adult; Multiple dose; Human; Agonist; Randomization; Healthy subject; Toxicity; β3-Adrenergic receptor; Placebo; Double blind study; Safety; Antiarrhythmic agent; Mirabegron
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/clpt.2012.181

Potential effects of the selective β3‐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.
Clinical Pharmacology & Therapeutics (2012); 92 6, 696–706. doi:10.1038/clpt.2012.181