Isavuconazonium

Identification

Summary

Isavuconazonium is a triazole antifungal used for the treatment of invasive aspergillosis and mucormycosis.

Brand Names
Cresemba
Generic Name
Isavuconazonium
DrugBank Accession Number
DB06636
Background

Isavuconazonium is a second-generation triazole antifungal approved on March 6, 2015 by the FDA for the treatment of invasive aspergillosis and invasive mucormycosis, marketed by Astellas under the brand Cresemba. It is the prodrug form of isavuconazole, the active moiety, and it is available in oral and parenteral formulations. Due to low solubility in water of isavuconazole on its own, the isovuconazonium formulation is favorable as it has high solubility in water and allows for intravenous administration. This formulation also avoids the use of a cyclodextrin vehicle for solubilization required for intravenous administration of other antifungals such as voriconazole and posaconazole, eliminating concerns of nephrotoxicity associated with cyclodextrin. Isovuconazonium has excellent oral bioavailability, predictable pharmacokinetics, and a good safety profile, making it a reasonable alternative to its few other competitors on the market.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 717.77
Monoisotopic: 717.241370179
Chemical Formula
C35H35F2N8O5S
Synonyms
  • Isavuconazonium
External IDs
  • BAL-8557
  • BAL8557

Pharmacology

Indication

Indicated in the treatment of invasive aspergillosis and invasive mucormycosis.

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Antifungals in the triazole class, such as isavuconazonium, target and inhibit the sterol 14-α-demethylase (Erg11p) which is a key player in the demethylation step of the ergosterol biosynthetic pathway. This inhibition results in a halt in production of ergosterol, a molecule typically found in the membranes of fungi such as Aspergillus, Candida, and Mucorales that plays a role in regulation of membrane integrity, fluidity and permeability. The inhibition of Erg11p also causes the buildup of ergosterol precursors, which are toxic and cause cell death.

Absorption

When administered intravenously as isavuconazonium, >99% of the prodrug is quickly converted to active isavuconazole (catalyzed by plasma esterases). Oral administration of isavuconazonium shows 98% oral bioavailability, however administration with food results in a 20% decrease in AUC (area under concentration-time curve) as well as decreasing maximum serum concentration (Cmax) by 50% and increasing time to Cmax by 1.5 hours.

Volume of distribution

450 L

Protein binding

>99%

Metabolism

Metabolism is primarily hepatic, with CYP3A4 and CYP3A5 involved in phase I metabolism, followed by modification by uridine diphosphate glucuronosyltransferase (UGT).

Route of elimination

45% excreted in feces and bile, and 45% excreted in urine as inactive metabolites. Less than 1% of active isavuconazole is excreted unchanged in urine.

Half-life

80 to 130 hours.

Clearance

Not Available

Adverse Effects
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Toxicity

Isavuconazole, the active moiety of isavuconazonium, is classified as Pregnancy Class C and should be avoided in pregnant women. It was also found to be excreted in breast milk in animal studies in rats, therefore it should be avoided in breastfeeding women.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be decreased when combined with Isavuconazonium.
AbametapirThe serum concentration of Isavuconazonium can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Isavuconazonium.
AbirateroneThe metabolism of Isavuconazonium can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Isavuconazonium.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Isavuconazonium.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Isavuconazonium.
AdagrasibThe metabolism of Adagrasib can be decreased when combined with Isavuconazonium.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Isavuconazonium.
AlbendazoleThe metabolism of Albendazole can be decreased when combined with Isavuconazonium.
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Food Interactions
  • Avoid grapefruit products. Grapefruit is a moderate to strong inhibitor of CYP3A4. Strong CYP3A4 inhibitors are contraindicated with isavuconazonium.
  • Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of isavuconazonium and may reduce its serum concentration. Co-administration of isavuconazonium with St. John's Wort is contraindicated.
  • Take with or without food. The bioavailability of isavuconazonium is not significantly impacted by food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Isavuconazonium sulfate31Q44514JV946075-13-4LWXUIUUOMSMZKJ-KLFWAVJMSA-M
Active Moieties
NameKindUNIICASInChI Key
Isavuconazoleprodrug60UTO373KE241479-67-4DDFOUSQFMYRUQK-RCDICMHDSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CresembaCapsule100 mgOralAvir Pharma Inc2019-05-02Not applicableCanada flag
CresembaCapsule186 mg/1OralAstellas Pharma US, Inc.2015-03-062017-01-31US flag
CresembaCapsule40 mg/1OralAstellas Pharma US, Inc.2022-11-22Not applicableUS flag
CresembaInjection, powder, lyophilized, for solution40 mg/1mLIntravenousAstellas Pharma US, Inc.2015-03-06Not applicableUS flag
CresembaPowder, for solution200 mg / vialIntravenousAvir Pharma Inc2019-05-31Not applicableCanada flag
CresembaCapsule100 mg/1OralAstellas Pharma US, Inc.2015-11-04Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as alpha amino acid esters. These are ester derivatives of alpha amino acids.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acid esters
Alternative Parents
Phenylpropanes / Benzonitriles / Fluorobenzenes / 2,4-disubstituted thiazoles / Imidolactams / Pyridines and derivatives / Aryl fluorides / Triazoles / Heteroaromatic compounds / Carbamate esters
show 14 more
Substituents
1,2,4-triazole / 2,4-disubstituted 1,3-thiazole / Alcohol / Alpha-amino acid ester / Amine / Aromatic alcohol / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle
show 32 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organic cation (CHEBI:85978)
Affected organisms
  • Candida albicans and other yeasts
  • Aspergillis, Candida and other fungi

Chemical Identifiers

UNII
VH2L779W8Q
CAS number
742049-41-8
InChI Key
RSWOJTICKMKTER-QXLBVTBOSA-N
InChI
InChI=1S/C35H35F2N8O5S/c1-22(33-42-30(18-51-33)25-9-7-24(15-38)8-10-25)35(48,28-14-27(36)11-12-29(28)37)19-45-21-44(20-41-45)23(2)50-34(47)43(4)32-26(6-5-13-40-32)17-49-31(46)16-39-3/h5-14,18,20-23,39,48H,16-17,19H2,1-4H3/q+1/t22-,23?,35+/m0/s1
IUPAC Name
1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[1-({methyl[3-({[2-(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium
SMILES
[H]C(C)(OC(=O)N(C)C1=C(COC(=O)CNC)C=CC=N1)[N+]1=CN(C[C@](O)(C2=C(F)C=CC(F)=C2)[C@@]([H])(C)C2=NC(=CS2)C2=CC=C(C=C2)C#N)N=C1

References

General References
  1. Rybak JM, Marx KR, Nishimoto AT, Rogers PD: Isavuconazole: Pharmacology, Pharmacodynamics, and Current Clinical Experience with a New Triazole Antifungal Agent. Pharmacotherapy. 2015 Nov;35(11):1037-51. doi: 10.1002/phar.1652. Epub 2015 Nov 2. [Article]
  2. Miceli MH, Kauffman CA: Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent. Clin Infect Dis. 2015 Nov 15;61(10):1558-65. doi: 10.1093/cid/civ571. Epub 2015 Jul 15. [Article]
  3. FDA Approved Drug Products: Cresemba (isavuconazonium sulfate) [Link]
KEGG Drug
D10643
PubChem Compound
6918606
PubChem Substance
310264875
ChemSpider
5293801
RxNav
1608322
ChEBI
85978
ChEMBL
CHEMBL1183349
Wikipedia
Isavuconazonium
FDA label
Download (851 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentInvasive Fungal Infections1
3CompletedTreatmentAspergillosis / Invasive Fungal Infections2
3CompletedTreatmentCandidemia / Candidiasis, Invasive / Mycoses1
3TerminatedPreventionCoronavirus Disease 2019 (COVID‑19) / Invasive Aspergillosis / Severe Acute Respiratory Syndrome Coronavirus 21
2CompletedPreventionAcute Myeloid Leukemia / Myelodysplastic Syndrome / Neutropenia1
2CompletedTreatmentCoronavirus Disease 2019 (COVID‑19) / Disseminated mucormycosis / Invasive Aspergillosis1
2CompletedTreatmentHematological Malignancy / Myeloproliferative Disorders (MPD)1
2RecruitingTreatmentCentral Nervous System Lymphoma1
2, 3CompletedPreventionAcute Myeloid Leukemia1
1CompletedNot AvailableHealthy Adult Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Ketoconazole1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral100 mg
CapsuleOral100 mg/1
CapsuleOral186 mg/1
CapsuleOral186.3 Mg
CapsuleOral40 mg/1
Injection, powder, for solutionIntravenous200 MG
Injection, powder, lyophilized, for solutionIntravenous40 mg/1mL
Powder, for solutionIntravenous200 mg / vial
Capsule, coatedOral186.3 mg
Injection, powder, lyophilized, for solutionIntravenous200 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7459561No2008-12-022020-10-31US flag
US6812238No2004-11-022020-10-31US flag
US10206879No2019-02-192027-09-14US flag
US10603280No2020-03-312027-09-14US flag
US10812238No2020-10-202025-10-31US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00516 mg/mLALOGPS
logP1.73ALOGPS
logP0.52Chemaxon
logS-5.2ALOGPS
pKa (Strongest Acidic)12.57Chemaxon
pKa (Strongest Basic)6.45Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count9Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area159.37 Å2Chemaxon
Rotatable Bond Count15Chemaxon
Refractivity193.86 m3·mol-1Chemaxon
Polarizability71.63 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
Curator comments
Isavuconazonium is a prodrug to Isavuconazole which is the actual CYP3A4 substrate, but it will therefore still participate in CYP3A4 drug interactions when taken.
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Rybak JM, Marx KR, Nishimoto AT, Rogers PD: Isavuconazole: Pharmacology, Pharmacodynamics, and Current Clinical Experience with a New Triazole Antifungal Agent. Pharmacotherapy. 2015 Nov;35(11):1037-51. doi: 10.1002/phar.1652. Epub 2015 Nov 2. [Article]
  2. CRESEMBA® (isavuconazonium sulfate) FDA Label [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Miceli MH, Kauffman CA: Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent. Clin Infect Dis. 2015 Nov 15;61(10):1558-65. doi: 10.1093/cid/civ571. Epub 2015 Jul 15. [Article]

Drug created at March 19, 2008 16:42 / Updated at March 21, 2023 17:58