Isavuconazonium is used to treat invasive aspergillosis and invasive mucormycosis in adults ages 18 years and older. It is available in a capsule for administration by mouth and as a powder for administration via infusion.
Contraindications
Isavuconazonium should not be given to anyone with a history of allergic reaction to it, nor to anyone taking ketoconazole or high-dose ritonavir. It should not be given to anyone with a family history of short QT syndrome. It has not been tested in children. In preclinical studies, isavuconazonium caused birth defects; it has not been tested in pregnant women. Women who are pregnant should not take it and women taking it should not get pregnant. It is excreted in breast milkso people should not breast feed while taking it.
Isavuconazonium is converted into isavuconazole inside the body, and isavuconazole is a substrate for CYP3A4 or CYP3A5. Many other medications inhibit or induce those two enzymes, and isavuconazonium should not be administered with them. Inducers result in levels of isavuconazole that are too low and won't work, and inhibitors can cause high levels of isavuconazole which will in turn cause increased adverse events and toxicity. Likewise isavuconazonium can interfere with appropriate dosing of other drugs that are substrates for those enzymes. In addition, isavuconazole induces CYP2B6 and can decrease the amount of drugs that are metabolized by the enzyme. Isavuconazole inhibits P-glycoprotein, BCRP, SLC22A2, and uridine diphosphate-glucuronosyltransferases, each of which remove drugs from circulation; isavuconazonium will increase the amount of drugs that are affected by those proteins and may increase their toxicities.
Pharmacology
After oral or IV administration, isavuconazonium is rapidly hydrolysed by esterases in blood or the gastrointestinal tract to the active form, isavuconazole. Isavuconazole works by inhibition of lanosterol 14α-demethylase, the enzyme responsible for converting lanosterol to ergosterol by demethylation. The resulting depletion of ergosterol and buildup of lanosterol compromise the structure of the fungal cell membrane. Mammalian cells are resistant to demethylation inhibition by azoles, making the drug effects specific to fungi.
Chemistry
Isavuconazonium comprises an N--N-methylamino-carboxymethyl group linked through an ester moiety to the triazole nitrogen in isavuconazole.
History
Isavuconazole and isavuconazonium were discovered in Japan by researchers at Roche's research center in Kamakura. Basilea Pharmaceutica, which had been spun out of Roche to develop antimicrobial assets, developed isavuconazonium through Phase II clinical trials. In February 2010, Basilea partnered with Astellas Pharma to complete Phase III trials, obtain regulatory approvals, and market the drug. In 2013 and 2014 the partners won orphan drug designation in the US for isavuconazonium for treating invasive aspergillosis, mucormycosis, and invasive candidiasis. In 2014 Basilea and Astellas amended the agreement to give Astellas sole marketing authority in North America, and Basilea the rights to market in the rest of the world. The FDA granted approval in March 2015 and the EMA approved it in October 2015. In 2017 Basilea licensed rights to Pfizer to sell in most of Europe and a few other countries.
