Isavuconazonium is a second-generation triazole antifungal approved on March 6, 2015 by the FDA for the treatment of invasive aspergillosis and invasive mucormycosis, marketed by Astellas under the brand Cresemba. It is the prodrug form of isavuconazole, the active moiety, and it is available in oral and parenteral formulations. Due to low solubility in water of isavuconazole on its own, the isovuconazonium formulation is favorable as it has high solubility in water and allows for intravenous administration. This formulation also avoids the use of a cyclodextrin vehicle for solubilization required for intravenous administration of other antifungals such as voriconazole and posaconazole, eliminating concerns of nephrotoxicity associated with cyclodextrin. Isovuconazonium has excellent oral bioavailability, predictable pharmacokinetics, and a good safety profile, making it a reasonable alternative to its few other competitors on the market.

• Combined Inhibitors of CYP3A4 and P-glycoprotein
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inducers (weak)
• Cytochrome P-450 CYP3A4 Inhibitors (moderate)
• Cytochrome P-450 CYP3A4 Substrates
• P-glycoprotein/ABCB1 Inhibitors

Indicated in the treatment of invasive aspergillosis and invasive mucormycosis.

• Disseminated mucormycosis
• INvasive Aspergillosis

Antifungals in the triazole class, such as isavuconazonium, target and inhibit the sterol 14-α-demethylase (Erg11p) which is a key player in the demethylation step of the ergosterol biosynthetic pathway. This inhibition results in a halt in production of ergosterol, a molecule typically found in the membranes of fungi such as Aspergillus, Candida, and Mucorales that plays a role in regulation of membrane integrity, fluidity and permeability. The inhibition of Erg11p also causes the buildup of ergosterol precursors, which are toxic and cause cell death.

When administered intravenously as isavuconazonium, >99% of the prodrug is quickly converted to active isavuconazole (catalyzed by plasma esterases). Oral administration of isavuconazonium shows 98% oral bioavailability, however administration with food results in a 20% decrease in AUC (area under concentration-time curve) as well as decreasing maximum serum concentration (Cmax) by 50% and increasing time to Cmax by 1.5 hours.

450 L

>99%

45% excreted in feces and bile, and 45% excreted in urine as inactive metabolites. Less than 1% of active isavuconazole is excreted unchanged in urine.

80 to 130 hours.

Isavuconazole, the active moiety of isavuconazonium, is classified as Pregnancy Class C and should be avoided in pregnant women. It was also found to be excreted in breast milk in animal studies in rats, therefore it should be avoided in breastfeeding women.

• Candida albicans and other yeasts
• Aspergillis, Candida and other fungi

1. Rybak JM, Marx KR, Nishimoto AT, Rogers PD: Isavuconazole: Pharmacology, Pharmacodynamics, and Current Clinical Experience with a New Triazole Antifungal Agent. Pharmacotherapy. 2015 Nov;35(11):1037-51. doi: 10.1002/phar.1652. Epub 2015 Nov 2. [PubMed:26598096 ]
2. Miceli MH, Kauffman CA: Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent. Clin Infect Dis. 2015 Nov 15;61(10):1558-65. doi: 10.1093/cid/civ571. Epub 2015 Jul 15. [PubMed:26179012 ]

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