Isavuconazole, a broad-spectrum triazole for the treatment of systemic fungal diseases

Abstract

The prodrug isavuconazonium sulfate (BAL8557) is an extended-spectrum water-soluble triazole, developed for the treatment of severe invasive and life-threatening fungal diseases. Its active moiety, BAL4815, is a potent inhibitor of ergosterol biosynthesis, resulting in the disruption of fungal membrane structure and function. The active compound shows broad-spectrum of activity and potency against all major opportunistic fungi, such as Aspergillus spp., Candida spp., Cryptococcus spp., Mucorales, Black yeasts and their filamentous relatives and the true pathogenic fungi, including Histoplasma capsulatum and Blastomyces dermatitidis. It is currently in Phase III clinical development for treatment of aspergillosis, candidiasis and mucormycosis, as well as other rare fungi infections. We reviewed the pharmacokinetic and pharmacodynamic characteristics of isavuconazole, and its microbiological and clinical investigation progress in advanced stages of development.

Keywords:

• isavuconazole
• pharmacodynamics
• pharmacokinetics
• systemic fungal infections

Financial & competing interests disclosure

S Seyedmousavi has received travel grants from Astellas Pharma B.V and Gilead Sciences. PE Verweij and JW Mouton have served as consultant to and have received research grants from Gilead Sciences, Merck B.V., Astellas Pharma B.V. and Pfizer B.V. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Isavuconazole is an investigational broad-spectrum antifungal drug with in vitro and in vivo activity against a broad range of yeasts and molds.

• Similar to other triazoles, isavuconazole acts by inhibiting the fungal CYP system.

• Both oral and intravenous formulations of isavuconazole consist of a water-soluble prodrug (isavuconazonium [BAL8557]) that is rapidly converted to isavuconazole (BAL4815) in plasma.

• Isavuconazole has a linear pharmacokinetics and a long half-life that allows once-daily administration.

• Intravenous isavuconazole does not require potentially nephrotoxic co-administration of cyclodextrin, which allows isavuconazole to be dosed in patients with renal impairment.

• Isavuconazole can be administered orally with minimal variability in its bioavailability that is not influenced by food intake.

• Although isavuconazole demonstrated very good activity against most of fungal species, its potency against Fusarium, Pseudallescheria and Scedosporium spp. is poor.

• The in vivo efficacy of isavuconazole was demonstrated against Aspergillus spp. and Candida spp., depending on both the drug exposure and on the isavuconazole MIC of the isolates.

• The exposure–response relationships of isavuconazole in experimental murine model of invasive Aspergillus and Candida infections demonstrated a very strong relationship between the PD index area under the concentration–time curve/MIC ratio and treatment outcome.

• Recent preclinical studies and data from case reports have shown the clinical effectiveness of isavuconazole against mucormycosis.

• Isavuconazole has shown potent in vitro activity against Cryptococcus spp., which suggests this agent as a promising alternative treatment in clinical practice. However, clinical data are needed to confirm these results.