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Isavuconazole (formerly also known as BAL-4815; RO-0094815; Cresemba), a water-soluble triazole antifungal agent, is a novel and potent inhibitor of CYP3A4 with broad-spectrum antifungal activity. Its prodrug, isavuconazonium sulfate (known also as BAL-8557), was approved by the U.S. Food and Drug Administration (FDA) on March 6, 2015 for the treatment of invasive candidiasis/aspergillosis and mucormycosis. 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.
Physicochemical Properties
| Molecular Formula | C22H17F2N5OS |
| Molecular Weight | 437.4651 |
| Exact Mass | 437.112 |
| Elemental Analysis | C, 60.40; H, 3.92; F, 8.69; N, 16.01; O, 3.66; S, 7.33 |
| CAS # | 241479-67-4 |
| Related CAS # | Isavuconazole-d4;1346598-58-0 |
| PubChem CID | 6918485 |
| Appearance | Solid powder |
| Density | 1.38 |
| Boiling Point | 678ºC at 760 mmHg |
| Flash Point | 363.8ºC |
| LogP | 4.242 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 31 |
| Complexity | 657 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | S1C([H])=C(C2C([H])=C([H])C(C#N)=C([H])C=2[H])N=C1[C@]([H])(C([H])([H])[H])[C@@](C1C([H])=C(C([H])=C([H])C=1F)F)(C([H])([H])N1C([H])=NC([H])=N1)O[H] |
| InChi Key | DDFOUSQFMYRUQK-RCDICMHDSA-N |
| InChi Code | 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 |
| Chemical Name | 4-(2-((2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)thiazol-4-yl)benzonitrile |
| Synonyms | BAL4815; RO0094815; BAL-4815; RO 0094815; BAL 4815; RO-0094815; Isavuconazole; trade name Cresemba. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | CYP3 |
| ln Vitro | Isavuconazole (BAL-4815) has an active MIC50 of 0.004 mg/L and exhibits good activity against all species of Candida. For Candida albicans, the MIC50s/MIC90s range from 0.002/0.004 mg/L to 0.25/0.5 mg/L[1]. Purpureocillium lilacinum, Scedosporium apiospermum, and the majority of common Aspergillus species are all effectively inhibited by isavuconazole in vitro[2]. Strong action is demonstrated by isavuconazole against yeasts, molds, and dimorphic fungi. The minimum inhibitory concentration (MIC) of isavuconazole for rhizopus isolates ranges from 0.12 µg/mL to 32 µg/mL [3]. Isavuconazole's modal minimum inhibitory concentrations (MICs) are 1, 8, 1, and 4 mg/L in the investigation of its pharmacokinetics and pharmacodynamics against the GFP transformants F/11628, NIH 4215, and F/16216, respectively[4]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Following oral administration of 200 mg isavuconazole, the mean peak plasma concentration (Cmax) at steady state was 7499 ng/mL. Cmax following oral administration of 600 mg isavuconazole was 20028 ng/mL. It is proposed that the Cmax at steady state is reached approximately 2–3 hours after single and multiple dosing of isavuconazole. Administration of 400 mg of oral and intravenous isavuconazole resulted in mean AUC of 189462.8 h*ng/mL and 193906.8 h*ng/mL, respectively. While isavuconazole can be administered with or without food, concurrent consumption of a high-fat meal reduced oral isavuconazole Cmax by 9% and increased AUC by 9%. The absolute bioavailability of isavuconazole following oral administration of a single dose of isavuconazole is 98%. Following oral administration, 46.1% of total radiolabelled isavuconzaole was detected in the feces, and about 45.5% was recovered in urine. Unchanged isavuconazole in the urine was less than 1% of the total dose administered. The mean steady state volume of distribution (Vss) was approximately 450 L following intravenous administration. The clearance (CL) rate was 2.5 ± 1.6 L/h in patients receiving 200 mg isavuconazole orally or intravenously. Metabolism / Metabolites Following rapid conversion of the prodrug isavuconazonium to isavuconazole via esterase-mediated hydrolysis, a number of minor metabolites were identified in addition to the active moiety itself and the inactive cleavage product of isavuconazonium. However, no individual metabolite was observed with an AUC greater than 10% of total radio-labeled material. The main enzymes involved in the metabolism of isavuconazole are CYP3A4, CYP3A5, and subsequently uridine diphosphate- glucuronosyltransferases (UGT) according to the findings of _in vivo_ and _in vitro_ studies. Biological Half-Life Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours. The mean half life following oral and intravenous administration of 400 mg isavuconazole was 110 and 115 hours, respectively. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of isavuconazole during breastfeeding. Because isavuconazole is more than 99% bound to plasma proteins, the amount in milk is likely to be low. However, there is no published experience with isavuconazole during breastfeeding, so an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin. |
| References |
[1]. In vitro activities of isavuconazole and other antifungal agents against Candida bloodstream isolates. Antimicrob Agents Chemother. 2007 May;51(5):1818-21. [2]. In Vitro Activity of Isavuconazole against Rasamsonia Species. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6890-6891. [3]. Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections. Infect Drug Resist. 2016 Jun 2;9:79-86. [4]. Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis. Antimicrob Agents Chemother. 2015 Oct 26;60(1):278-87. [5]. Evaluation of the pharmacokinetics and clinical utility of isavuconazole for treatment of invasive fungal infections. Expert Opin Drug Metab Toxicol. 2012 Jun;8(6):759-65. |
| Additional Infomation |
Pharmacodynamics Isavucoanzole exhibits antifungal activity against most strains of _Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger_, and Mucorales such as _Rhizopus oryzae_ and Mucormycetes species _in vivo_ and _in vitro_. In a cardiac electrophysiology study involving healthy subjects, isavuconazole induced dose-related shortening of the QTc interval but the additive effect of isavuconazole with other QTc-prolonging drug is unknown. |
Solubility Data
| Solubility (In Vitro) |
DMSO : 50~87 mg/mL ( 114.29~198.87 mM ) Ethanol : ~87 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.71 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.71 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2859 mL | 11.4294 mL | 22.8587 mL | |
| 5 mM | 0.4572 mL | 2.2859 mL | 4.5717 mL | |
| 10 mM | 0.2286 mL | 1.1429 mL | 2.2859 mL |