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)
AHFS/Drugs.com entry
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 Oral, intravenous
Legal status
Legal status
Identifiers
ATC code J02AC05 (WHO)
PubChem CID 6918485
ChemSpider 5293682 N
UNII 60UTO373KE N
ChEBI CHEBI:85979 YesY
ChEMBL CHEMBL409153 N
NIAID ChemDB 416566
Chemical data
Formula C22H17F2N5OS
Molar mass 437.47 g/mol
 NYesY (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]

Medical uses

Isavuconazole 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.[5][6]

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

Rare

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.

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.[8]

Clinical trials

There have been three phase III clinical trials of isavuconazole, ACTIVE, VITAL and SECURE. As of June 2015, SECURE and VITAL have been presented in abstract form and results from ACTIVE have not been released.[9]

The SECURE trial compared voriconazole and isavuconazole in invasive fungal infections due to aspergillus. Isuvaconazole was found to be non-inferior to voriconazole, another triazole antifungal, with all cause mortality at 18.6%, compared to 20.2% in the voriconazole group. It additionally demonstrated a similar side effect profile.[10][11] A commentary on the study noted that "Isavuconazole will probably achieve an equivalent recommendation to voriconazole for the initial treatment of invasive aspergillosis in clinical guidelines. However, voriconazole will become off-patent in many countries from 2016 and new formulations of posaconazole are now available, broadening therapeutic options and affecting cost."[12]

References

  1. ↑
  2. ↑ Saboo, Alok. "Basilea Announces Global Partnership With Astellas for Its Antifungal Isavuconazole." FierceBiotech. N.p., 24 Feb. 2010. Web.
  3. ↑ "Basilea reports isavuconazole orphan drug designation by U.S. FDA." Market Wired. 28 May 2013.
  4. ↑ "FDA Grants Orphan Drug Designation to Astellas for Isavuconazole for the Treatment of Invasive Candidiasis." News Releases. Astellas. 3 Nov 2014.
  5. ↑ "Aspergillosis." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 08 Sept. 2014.
  6. ↑ "Astellas Receives FDA Approval for CRESEMBA® (isavuconazonium Sulfate) for the Treatment of Invasive Aspergillosis and Invasive Mucormycosis." PR Newswire. N.p., 6 Mar. 2015.
  7. ↑ "Isavuconazonium." Micromedex Solutions. Truven Health Analytics, n.d. Web. <www.micromedexsolutions.com>.
  8. ↑ Cresemba (isovuconazole sulfate) [prescribing information]. Astella Pharma US, Inc. Revised March 2015.
  9. ↑ Pettit, Natasha N.; Carver, Peggy L. (2015-07-01). "Isavuconazole A New Option for the Management of Invasive Fungal Infections". Annals of Pharmacotherapy 49 (7): 825–842. doi:10.1177/1060028015581679. ISSN 1060-0280. PMID 25940222.
  10. ↑ Mujais, A. "2014: M-1756. A Phase 3 Randomized, Double-Blind, Non-Inferiority Trial Evaluating Isavuconazole (ISA) vs. Voriconazole (VRC) for the Primary Treatment of Invasive Fungal Disease (IFD) Caused by Aspergillus spp. or other Filamentous Fungi (SECURE): Outcomes by Malignancy Status". www.icaaconline.com. Retrieved 2015-06-19.
  11. ↑ Maertens, Johan A; Raad, Issam I; Marr, Kieren A; Patterson, Thomas F; Kontoyiannis, Dimitrios P; Cornely, Oliver A; Bow, Eric J; Rahav, Galia; Neofytos, Dionysios. "Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial". The Lancet. doi:10.1016/s0140-6736(15)01159-9.
  12. ↑ Slavin, Monica A; Thursky, Karin A. "Isavuconazole: a role for the newest broad-spectrum triazole". The Lancet. doi:10.1016/s0140-6736(15)01218-0.
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