QT Interval Shortening With Isavuconazole: In Vitro and In Vivo Effects on Cardiac Repolarization

• Published in: Clinical pharmacology and therapeutics 2017-06, Vol.101 (6), p.782-790
• Main Authors: Keirns, J, Desai, A, Kowalski, D, Lademacher, C, Mujais, S, Parker, B, Schneidkraut, MJ, Townsend, R, Wojtkowski, T, Yamazaki, T, Yen, M, Kowey, PR
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Adult; Antifungal Agents - adverse effects; Antifungal Agents - pharmacokinetics; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - physiopathology; Calcium Channel Blockers - adverse effects; Calcium Channel Blockers - pharmacokinetics; Calcium Channels, L-Type - drug effects; Calcium Channels, L-Type - metabolism; Cell Line; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Heart Conduction System - drug effects; Heart Conduction System - metabolism; Heart Conduction System - physiopathology; Heart Rate - drug effects; Humans; Male; Models, Biological; Nitriles - adverse effects; Nitriles - pharmacokinetics; Pyridines - adverse effects; Pyridines - pharmacokinetics; Risk Assessment; Time Factors; Transfection; Triazoles - adverse effects; Triazoles - pharmacokinetics; Young Adult
• ISSN: 0009-9236; 1532-6535; 1532-6535
• DOI: 10.1002/cpt.620

The effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a phase I, randomized, double‐blind study in healthy individuals who received isavuconazole (after 2‐day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg q.d.), or placebo. A post‐hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L‐type Ca2+ channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximum serum concentrations of nonprotein‐bound isavuconazole in vivo. In the phase I study (n = 161), isavuconazole shortened the QT interval in a dose‐ and plasma concentration‐related manner. There were no serious treatment‐emergent adverse events; palpitations and tachycardia were observed in placebo and supratherapeutic isavuconazole groups; no cardiac safety signals were detected in the SECURE study (n = 257). Isavuconazole was associated with a shortened cardiac QT interval.