Fungal Infections

Isavuconazole

Isavuconazonium sulfate (Cresemba) is the prodrug of isavuconazole, an azole antifungal drug, that prevents the formation of ergosterol, necessary for the cell membranes of fungi, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase. FDA and EMA have approved isavuconazole for the treatment of invasive aspergillosis and invasive mucormycosis for patients 18 years of age and older in 2015.

Dose & Delivery

Isavuconazonium sulfate (isavuconazole prodrug) is available as intravenous and oral drug.

·         One vial for intravenous injection contains 372 mg of isavuconazonium sulfate equivalent to 200 mg of isavuconazole;

·         One capsule for oral administration contains 186 mg of isavuconazonium sulfate equivalent to 100 mg of isavuconazole.

The following table explains the dosage regimen

 

Loading dose

Maintenance dose

Intravenous  and oral

200 mg of isavuconazole every 8 hours for 48 hours (6 doses in total)

200 mg of isavuconazole once daily, starting 12-24 hours after the last loading dose

It is not necessary to give a loading dose when a switch from intravenous to oral administration is made; bioequivalence has been demonstrated. There is no need for dose adjustment based on age, gender or race, renal impairment or mild to moderate hepatic disease. However, the pharmacokinetics in paediatric patients or those with severe hepatic impairment (Child-Pugh Class C) have not been done.

There is no data in pregnant woman, and it is not recommended. Isavuconazole is excreted in the milk of lactating rats, thus mothers should not breastfeed while taking isavuconazole.

When administered by intravenous route, it must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron) and be infused over 1 hour.

Fungi - the drug is active against

Isavuconazole has in vitro activity against Aspergillus fumigatus, A. flavus, A. terreus, A. niger and A. nidulans. Besides, it has also activity against Histoplasma capsulatum, Coccidioides immitis and Blastomyces dermatitidis as well as Candida spp, Cryptococcus spp and Trichosporon spp. The in vitro activity against Mucorales. Fusarium spp and Scedosporium apiospermum is variable. Finally, it has also in vitro activity against fungi causing phaeohyphomycosis and chromoblastomycosis.

Metabolism, distribution and excretion

After oral administration of the prodrug in healthy volunteers, isavuconazole reaches maximum plasma concentrations 2-3 hours after single and multiple dosing with an estimated bioavailability of 98%. Food does not have any effect in the absorption of the prodrug. Isavuconazonium sulfate (the prodrug) is rapidly hydrolysed to isavuconazole by esterases. There is no significant concentration of the prodrug or inactive cleavage products in the plasma after oral administration.

Isavuconazole is metabolised primarily by the liver. It is a substrate of cytochrome P450 enzymes 3A4 and 3A5. Isavuconazole has a very large apparent volume of distribution suggesting extensive tissue uptake and is highly protein bound (>99%). The elimination half-life is ~130 hours and requires a loading dose regimen to rapidly achieve steady-state Excretion of isavuconazole is mainly in faeces. Less than 1% of the doses administered is excreted in the urine.

Drug/Drug interactions

Isavuconazole has fewer interaction with other drugs than other azole antifungals. Isavuconazole is an inhibitor of CYP3A4. If administered with strong CYP3A4 inhibitors, such lopinavir/ritonavir, the plasma concentration of isavuconazole can significantly be increased. Coadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates can significantly decrease the plasma concentration of isavuconazole. Isavuconazole decreases the concentrations of lopinavir/ritonavir and bupropion.

Isavuconazole can increase the concentrations of atorvastatin, ciclosporin, sirolimus, tacrolimus, midazolam, mycophenolate mofetil, and digoxin. Monitoring drug concentrations and/or doses adjustment can be needed. View drug interactions database 

Side effects

The most frequently side effects of isavuconazole in decreasing order are nausea, vomiting, diarrhoea, headache, elevated liver tests, hypokalaemia, constipation, dyspnoea, cough, peripheral oedema and back pain.

Structure of isavuconazole

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