Isavuconazole

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Isavuconazole
280px
280px
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)
Legal status
Routes of
administration		 Oral, intravenous
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
Molecular mass 437.47 g/mol
  • 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=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
 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]

Isavuconazonium sulfate (BAL8557)—a prodrug of isavuconazole.

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

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.[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

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]

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.[13]

The ACTIVE trial is a comparison of isuvaconazole and caspofungin for invasive candida infections and results are anticipated in the second half of 2015.[14][15] Preliminary results released by Astellas indicate that isuvaconazole did not reach non-inferiority to caspofungin but that further analysis was pending.[16]

References

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  1. ↑ [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. ↑ Cresemba (isovuconazole sulfate) [prescribing information]. Astella Pharma US, Inc. Revised March 2015.
  6. ↑ "Aspergillosis." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 08 Sept. 2014.
  7. ↑ "Astellas Receives FDA Approval for CRESEMBA® (isavuconazonium Sulfate) for the Treatment of Invasive Aspergillosis and Invasive Mucormycosis." PR Newswire. N.p., 6 Mar. 2015.
  8. ↑ "Isavuconazonium." Micromedex Solutions. Truven Health Analytics, n.d. Web. <www.micromedexsolutions.com>.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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