Isavuconazonium
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
Structure for Isavuconazonium (DB06636)
- Synonyms
- Isavuconazonium
- External IDs
- BAL-8557 / BAL8557
- Product Ingredients
Ingredient UNII CAS InChI Key Isavuconazonium sulfate 31Q44514JV 946075-13-4 LWXUIUUOMSMZKJ-KLFWAVJMSA-M - Active Moieties
Name Kind UNII CAS InChI Key Isavuconazole prodrug 60UTO373KE 241479-67-4 DDFOUSQFMYRUQK-RCDICMHDSA-N - Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Cresemba Capsule 186 mg/1 Oral Astellas Pharma Inc 2015-03-06 2016-12-31 US 
Cresemba Injection, powder, lyophilized, for solution 74.4 mg/1mL Intravenous Astellas Pharma Inc 2015-03-06 Not applicable US Cresemba Capsule 186 mg/1 Oral Astellas Pharma Inc 2015-11-04 Not applicable US - Categories
- Antifungal Agents
- Azole Antifungals
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (moderate)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- P-glycoprotein/ABCB1 Inhibitors
- 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
Drug Interaction (R)-warfarin The metabolism of (R)-warfarin can be decreased when combined with Isavuconazonium. (S)-Warfarin The metabolism of (S)-Warfarin can be decreased when combined with Isavuconazonium. 3,5-diiodothyropropionic acid The metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Isavuconazonium. 4-hydroxycoumarin The metabolism of 4-hydroxycoumarin can be increased when combined with Isavuconazonium. 5-androstenedione The metabolism of 5-androstenedione can be decreased when combined with Isavuconazonium. 6-Deoxyerythronolide B The metabolism of Isavuconazonium can be decreased when combined with 6-Deoxyerythronolide B. 6-O-benzylguanine The metabolism of 6-O-benzylguanine can be decreased when combined with Isavuconazonium. 7-ethyl-10-hydroxycamptothecin The metabolism of 7-ethyl-10-hydroxycamptothecin can be decreased when combined with Isavuconazonium. 9-aminocamptothecin The metabolism of 9-aminocamptothecin can be decreased when combined with Isavuconazonium. Abatacept The metabolism of Isavuconazonium can be increased when combined with Abatacept. - Food Interactions
- Not Available
References
- General References
- 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]
- 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
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Capsule Oral 186 mg/1 Injection, powder, lyophilized, for solution Intravenous 74.4 mg/1mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) US7459561 No 2008-12-02 2020-10-31 US US6812238 No 2004-11-02 2020-10-31 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00516 mg/mL ALOGPS logP 1.73 ALOGPS logP 0.52 ChemAxon logS -5.2 ALOGPS pKa (Strongest Acidic) 12.57 ChemAxon pKa (Strongest Basic) 6.45 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 9 ChemAxon Hydrogen Donor Count 2 ChemAxon Polar Surface Area 159.37 Å2 ChemAxon Rotatable Bond Count 15 ChemAxon Refractivity 193.86 m3·mol-1 ChemAxon Polarizability 71.63 Å3 ChemAxon Number of Rings 5 ChemAxon Bioavailability 0 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - Predicted ADMET features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not 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
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitorInducer
- 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
- 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]
- CRESEMBA® (isavuconazonium sulfate) FDA Label [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- 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
- 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 December 16, 2018 06:53