Isavuconazole: A new broad-spectrum azole. Part 2: pharmacokinetics and clinical activity

Isavuconazole, the active moiety of its prodrug isavuconazonium, is a new extended-spectrum triazole whose activity against yeasts, molds, including Aspergillus and mucorales, and dimorphic fungi has been shown in vitro and in preclinical models. The most relevant pharmacokinetics features are water-solubility of the prodrug, rapid cleavage of the prodrug into active moiety and cleavage product by plasmatic esterases, high oral bioavailability of isavuconazole with an extensive penetration into most tissues and a good safety profile even in case of renal impairment. The results of two main clinical studies have led to an approval by FDA and EMA in the treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazole is non-inferior to voriconazole in terms of response and survival in invasive aspergillosis and has shown improved safety and tolerability. Importantly, less hepatobiliary, skin and eye disorders have been reported in isavuconazole-treated patients. Isavuconazole has therefore been granted a grade A-I recommendation by the European Conference on Infections in Leukemia (ECIL) for the treatment of invasive aspergillosis. Efficacy has also been demonstrated in mucormycosis in an open-label study. Survival was similar to the survival of matched patients from the international Fungiscope registry and treated with an amphotericin B formulation. Isavuconazole failed to show non-inferiority to caspofungin in a large double-blind candidemia trial. The aim of this review is to give the reader an overview of the data available so far to support inclusion of isavuconazole in the anti-mold therapeutic arsenal.