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Newer antifungal agents in pediatrics
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Isavuconazole, formulated in IV and oral capsule preparations as a prodrug, isavuconazonium sulfate, was approved by the FDA in 2015 for treatment of invasive aspergillosis and mucormycosis in adults. It has a broad spectrum of activity including Candida, Cryptococcus, Aspergillus, and the Mucorales. The prodrug, isavuconazonium, is rapidly cleaved by plamsa esterases to isavuconazole. Oral bioavailability is 98% with low intersubject variability and no clinically significant food effect. It is water soluble with high protein binding, a large volume of distribution indicating likely high tissue penetration. It exhibits dose-proportional pharmacokinetics with moderate deviation from linearity. Elimination is primarily though hepatic metabolism; its prolonged half-life allows once daily dosing following initial loading doses [49,50]. Because it is highly water soluble, the IV formulation of isavuconazole does not require the SBECD carrier that is needed for voriconazole and posaconazole IV formulations; thus it can be used in the setting of significant renal impairment without risk of accumulation.
Avenues for antifungal drug discovery and development: where to now?
Published in Expert Opinion on Drug Discovery, 2022
Stephanos Vassilopoulos, Eleftherios Mylonakis
Regarding new indications for existing antifungal agents, isavuconazole (administered in the form of the prodrug isavuconazonium sulfate) is a second-generation broad spectrum triazole recently approved by the Food and Drug Administration (FDA) for adults with invasive aspergillosis and invasive mucormycosis. Isavuconazole has been shown to effectively treat invasive aspergillosis, invasive mucormycosis, and infections by Candida spp and has a better side effect profile and improved pharmacokinetics compared with other broad-spectrum azoles [34]. Currently, isavuconazole is under evaluation for the treatment of pediatric patients with invasive aspergillosis or invasive mucormycosis (NCT03816176) as well as for prophylaxis against pulmonary aspergillosis associated with COVID-19 (NCT04707703) [35].
Evolution of antifungals for invasive mold infections in immunocompromised hosts, then and now
Published in Expert Review of Anti-infective Therapy, 2023
Zoe Freeman Weiss, Jessica Little, Sarah Hammond
Isavuconazonium sulfate, a prodrug containing mold-active isavuconazole, was FDA-approved in 2015 for treatment of aspergillosis and mucormycosis. The intravenous formulation of isavuconazole does not contain cyclodextrin and thus may be safer in patients with diminished creatinine clearance. Isavuconazole has excellent oral bioavailability and achieves predictable drug levels in adults, potentially reducing the need for therapeutic drug level monitoring. Unlike other azole antifungals, isavuconazole does not prolong the QTC interval and may even shorten it, though the clinical significance of this effect is unknown. Hepatotoxicity and drug interactions with other CYP3A4 metabolized agents, though less common than with other triazoles, are still a concern [24].
Successes, failures, and future prospects of prodrugs and their clinical impact
Published in Expert Opinion on Drug Discovery, 2019
Isavuconazonium is a recently approved second generation azole antifungal and a prodrug of isavuconazole. Following oral or intravenous administration, the prodrug is rapidly and completely converted by plasma esterase. Isavuconazole is an inhibitor of 14-α-demethylase, a membrane protein involved in ergosterol biosynthesis [64,65]. It is indicated for the treatment of aspergillosis and mucormycosis. Isavuconazonium has better water solubility than its parent compound, and hence it is available intravenously.