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

摘要

The effects of isavuconazole (active moiety of isavuconazoniumsulfate) 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 (400mg q. d.), or placebo. A post-hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L-type Ca21 channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximumserumconcentrations of nonprotein-bound isavuconazole in vivo. In the phase I study (n5161), 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 (n5257). Isavuconazole was associated with a shortened cardiac QT interval.