Isavuconazole

Isavuconazole

Systematic (IUPAC) name
4-{2-[(1R,2R)-(2,5-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile
Clinical data
Trade names	Cresemba (prodrug form)
Legal status	US: ℞-only ℞ (Prescription only)
Routes of administration	Oral; Intravenous
Identifiers
CAS Registry Number	Y
ATC code	None
PubChem	CID 6918485
ChemSpider	5293682 N
UNII	60UTO373KE N
ChEMBL	CHEMBL409153 N
NIAID ChemDB	416566
Chemical data
Formula	C22H17F2N5OS
Molecular mass	437.47 g/mol
SMILES C[C@@H](C1=NC(=CS1)C2=CC=C(C=C2)C#N)[C@](CN3C=NC=N3)(C4=C(C=CC(=C4)F)F)O
InChI InChI=1S/C22H17F2N5OS/c1-14(21-28-20(10-31-21)16-4-2-15(9-25)3-5-16)22(30,11-29-13-26-12-27-29)18-8-17(23)6-7-19(18)24/h2-8,10,12-14,30H,11H2,1H3/t14-,22+/m0/s1  N Key:DDFOUSQFMYRUQK-RCDICMHDSA-N  N
N (what is this?)  (verify)

Isavuconazole (BAL4815; trade name Cresemba) is a triazole antifungal drug. Its prodrug, isavuconazonium sulfate (BAL8557), was granted approval by the U.S. Food and Drug Administration (FDA) on March 6, 2015^[1]

During its Phase III drug trials, Astellas partnered with Basilea Pharmaceutica, the developer of the drug, for rights to co-development and marketing of isavuconazole. ^[2]

On May 28, 2013, Basilea Pharmaceutica announced it had been granted orphan drug status by the FDA for treatment of aspergillosis.^[3] Since then, it has also been granted orphan drug status for the treatment of invasive candidiasis.^[4]

Mechanism of Action

Isavuconazole works by inhibiting lanosterol 14 alpha-demethylase, the enzyme responsible for converting lanosterol to ergosterol by demethylation. The resulting depletion of ergosterol and build up 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.^[5]

Indications for Use

Isovuconazole has been approved by the FDA for treatment of invasive aspergillosis and invasive mucormycosis in adults ages 18 years and older. Both infections are caused by mold and fungi common to the environment, and occur in individuals who are immunosuppressed or have other complicating conditions, such as diabetes or lung disease.^[6][7]

Dosing

The intravenous (IV) and oral formulations of isovuconazole are bioequivalent, so formulations may be switched between without an additional loading dose.

Side Effects

Common

• Cardiovascular: peripheral edema
• Endocrine: hypokalemia
• Gastrointestinal: constipation, diarrhea, nausea, vomiting
• Musculoskeletal: backache
• Neurologic: headache
• Respiratory: cough

Rare

• Hepatic: cholestasis, hepatitis, increased liver function tests, liver failure
• Immunologic: hypersensitivity reaction
• Renal: renal failure
• Respiratory: acute respiratory failure
• Other: infusion reaction (IV only)^[8]

Warnings

Isavuconazole should not be administered with other medications that strongly inhibit or induce the enzyme CYP3A4 due to the effect on plasma concentration. CYP3A4 inducers can result in subtherapeutic drug levels, and CYP3A4 inhibitors can cause supratherapeutic levels with increased adverse events and toxicity.

Studies have shown isavuconazole to have a dose dependent effect of shortening the QTc interval. It is contraindicated for use in individuals with familial short QT syndrome. Additive effects with other drugs that shorten the QTc have not been evaluated.

Clinical Trials

Isovuconazole was demonstrated in Phase III clinical trial SECURE to be non-inferior to voriconazole, another triazole antifungal, in the treatment of invasive aspergillosis, with all cause mortality at 18.6%, compared to 20.2% in the comparator group. It additionally demonstrated a similar side effect profile.

Data from the VITAL study showed that isavuconazole could be used in treatment of invasive mucormycosis, but did not evaluate its clinical efficacy for this indication.

References