Isavuconazole shortens the QTc interval

Abstract

Isavuconazole is a novel antifungal drug approved for the treatment of adults with invasive aspergillosis and mucormycosis. While azoles as a class effect are known to prolong QTc interval, clinical trials have shown that isavuconazole administration may cause shortening in a dose-related manner. Here, we assessed the effects of isavuconazole on the length of QTc interval. The objective of the study was to describe changes in the QTc interval induced by isavuconazole treatment. A total of 26 adult patients from 7 hospitals were included. Patients received isavuconazole for the treatment of invasive fungal infection and, in 1 case, for prophylaxis due to QTc prolongation under fluconazole. Twelve-channel electrocardiograms (ECGs) were performed before and during treatment. Out of 26 patients, 24 showed shortening of QTc interval. In patients with QTc shortening, QTc during isavuconazole treatment showed a mean decrease of 7.4 ± 5.8% (36.5 ± 38.8 ms, range 7-202; P = .004), compared to pre-isavuconazole ECG. One patient with available long-term follow-up showed further decrease in QTc on days 55 and 110. Apart from 1 case report, these are the first data outside controlled clinical trials showing QTc shortening. Knowledge about cardiac effects of isavuconazole will serve to better manage the use of concomitant medications.

Spotlight on isavuconazole in the treatment of invasive aspergillosis and mucormycosis: design, development, and place in therapy

“…24 Given the potential for isavuconazole to shorten the QTc interval, it should be prescribed with caution when prescribed with medications known to shorten the QTc interval. 47 , 48 …”

“… 29 , 47 This was recently confirmed by a smaller study reporting that 24 out of 26 patients treated with isavuconazole developed a shortened QTc interval with a mean decrease of 36.5±38.8 ms (7.4%±5.8%) compared to the pre-isavuconazole electrocardiogram. 48 …”

EQUAL Aspergillosis Score 2018: An ECMM score derived from current guidelines to measure QUALity of the clinical management of invasive pulmonary aspergillosis

“…For targeted first line treatment of invasive pulmonary aspergillosis isavuconazole or voriconazole with therapeutic drug monitoring (TDM) is recommended (five points) . Voriconazole target plasma trough range is 1‐5.5 mg/L .…”

Treatment of Chronic Pulmonary Aspergillosis: Current Standards and Future Perspectives

“…QTc interval prolongation has been described for voriconazole, intraconazole and posaconazole, and may be potentiated if those azoles are administered together with quinolones [19][20][21]. In contrast, isavuconazole is associated with a shortened QTc interval with a mean decrease of 36.5 ± 38.8 ms (7.4 ± 5.8%) compared to the pre-isavuconazole electrocardiogram in a recent study [22]. Overall, isavuconazole has been shown in clinical trials and also a limited number of real life studies to be better tolerated than particularly voriconazole and itraconazole and may therefore be a viable oral alternative in patients experiencing adverse events [23].…”

“…The ECIL-6 guideline recommends it as first-line therapy for invasive aspergillosis in patients with hematological malignancies (AI -AII recommendation), and the IDSA recommends it as an alternative treatment [7,28]. The main advantages of isavuconazole compared to voriconazole are: (a) reduced nephrotoxicity in patients given intravenous therapy; (b) no required dose adjustments in patients with renal and hepatic dysfunction; (c) fewer drug-drug interactions, only interactions with CYP3A4 inducers or inhibitors; and (d) no contribution to a prolonged QTc interval (isavuconazole shortens the QTc interval) [18,22,50].…”