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

摘要

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.