Identification

Name
Isavuconazonium
Accession Number
DB06636
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
Synonyms
Not Available
External IDs
BAL-8557 / BAL8557
Product Ingredients
IngredientUNIICASInChI Key
Isavuconazonium sulfate31Q44514JV946075-13-4LWXUIUUOMSMZKJ-KLFWAVJMSA-M
Active Moieties
NameKindUNIICASInChI Key
Isavuconazoleprodrug60UTO373KE241479-67-4DDFOUSQFMYRUQK-RCDICMHDSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CresembaCapsule186 mg/1OralAstellas Pharma Inc2015-11-04Not applicableUs
CresembaInjection, powder, lyophilized, for solution74.4 mg/1mLIntravenousAstellas Pharma Inc2015-03-06Not applicableUs
CresembaCapsule186 mg/1OralAstellas Pharma Inc2015-03-062016-12-31Us
Categories
UNII
VH2L779W8Q
CAS number
742049-41-8
Weight
Average: 717.77
Monoisotopic: 717.241370179
Chemical Formula
C35H35F2N8O5S
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

Pharmacology

Indication

Indicated in the treatment of invasive aspergillosis and invasive mucormycosis.

Associated Conditions
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
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.

Affected organisms
  • Candida albicans and other yeasts
  • Aspergillis, Candida and other fungi
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Isavuconazonium.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Isavuconazonium.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Isavuconazonium.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Isavuconazonium.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Isavuconazonium.
6-Deoxyerythronolide BThe metabolism of Isavuconazonium can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Isavuconazonium.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Isavuconazonium.
AbataceptThe metabolism of Isavuconazonium can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Isavuconazonium.
Food Interactions
Not Available

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. [PubMed:26598096]
  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. [PubMed:26179012]
External Links
KEGG Drug
D10643
PubChem Compound
6918606
PubChem Substance
310264875
ChemSpider
5293801
ChEBI
85978
ChEMBL
CHEMBL1183349
Wikipedia
Isavuconazole
FDA label
Download (851 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Adult Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Ketoconazole1
1CompletedNot AvailableHealthy Volunteers1
1CompletedNot AvailableHealthy Volunteers / Pharmacodynamics of Warfarin / Pharmacokinetics of Isavuconazole / Pharmacokinetics of S- and R-warfarin1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of 14C-labeled Isavuconazonium Sulfate1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of 7-hydroxymethotrexate / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Methotrexate1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Atorvastatin / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of BAL4815 / Pharmacokinetics of BAL87281
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Bupropion / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Digoxin / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Ethinyl Estradiol and Norethindrone / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Lopinavir/Ritonavir1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Metformin1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Methadone1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Midazolam1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Prednisolone1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Sirolimus1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Tacrolimus1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Renal Impaired1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Safety and Tolerability in Elderly1
1RecruitingTreatmentHaematological Malignancies1
2Active Not RecruitingTreatmentMalignancies, Hematologic / Myeloproliferative Disorders1
2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML) / Myelodysplastic Syndrome1
2, 3CompletedPreventionLeukemia Acute Myeloid Leukemia (AML)1
3CompletedTreatmentAspergillosis / Invasive Fungal Infections2
3CompletedTreatmentCandidemia / Candidiasis, Invasive / Mycoses1
Not AvailableRecruitingNot AvailableInvasive Fungal Infections1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral186 mg/1
Injection, powder, lyophilized, for solutionIntravenous74.4 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7459561No2008-12-022020-10-31Us
US6812238No2004-11-022020-10-31Us

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

Taxonomy

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
Alpha-amino acid ester / Phenylpropane / Benzonitrile / 2,4-disubstituted 1,3-thiazole / Fluorobenzene / Halobenzene / Aryl fluoride / Aryl halide / Pyridine / Imidolactam
show 32 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organic cation (CHEBI:85978)

Enzymes

Kind
Protein
Organism
Human
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. [PubMed:26598096]
  2. CRESEMBA® (isavuconazonium sulfate) FDA Label [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Yes
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. [PubMed:26179012]

Drug created on March 19, 2008 10:42 / Updated on November 02, 2018 08:46