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

Abstract

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.

The cost-effectiveness of isavuconazole compared to the standard of care in the treatment of patients with invasive fungal infection prior to differential pathogen diagnosis in the United Kingdom

“…Importantly, a number of clinical, pharmacokinetic, pharmacodynamic, safety and ease-of-use benefits have been documented with the use of isavuconazole, which fall outside of the scope of the model described here. For example, unlike voriconazole which may extend the QT interval, isavuconazole has a dose-related shortening effect, with no evidence of associated cardiac risk, thereby potentially reducing the cost of cardiac-associated AEs 67 . Additionally, isavuconazole has fixed dose administration via either oral capsules or an intravenous infusion 33 , whereas voriconazole must be administered twice daily, which will likely lead to increased costs associated with drug administration.…”

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“…Cardiotoxicity: QT prolongation is a standard parameter to study cardiac abnormalities 103 . Further, prolongation of QT may be responsible for the sudden death and it is called Torsade de Pointes 104 .…”

Isavuconazole shortens the QTc interval

“…The drug has been approved by the US and the European regulatory agencies in 2016. While azoles as a class effect are known to prolong QTc interval, clinical trials have shown that isavuconazole administration may shorten QTc interval in a dose‐related manner …”

“…While azoles as a class effect are known to prolong QTc interval, [1][2][3] clinical trials have shown that isavuconazole administration may shorten QTc interval in a dose-related manner. 4,5 The QT interval is a measure of time in electrocardiograms (ECGs) and describes the duration of the cellular action potential. 6 Due to its variation with heart rate, the QT interval must be corrected before interpretation.…”