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Purity: ≥98%
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.
| Targets |
CYP3
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|---|---|
| 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].
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| 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 |
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| 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. |
| Molecular Formula |
C22H17F2N5OS
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|---|---|
| Molecular Weight |
437.4651
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| Exact Mass |
437.112
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| Elemental Analysis |
C, 60.40; H, 3.92; F, 8.69; N, 16.01; O, 3.66; S, 7.33
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| CAS # |
241479-67-4
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| Related CAS # |
Isavuconazole-d4;1346598-58-0
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| PubChem CID |
6918485
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| Appearance |
Solid powder
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| Density |
1.38
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| Boiling Point |
678ºC at 760 mmHg
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| Flash Point |
363.8ºC
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| LogP |
4.242
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
657
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| Defined Atom Stereocenter Count |
2
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| 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]
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| InChi Key |
DDFOUSQFMYRUQK-RCDICMHDSA-N
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| 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
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| 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
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| Synonyms |
BAL4815; RO0094815; BAL-4815; RO 0094815; BAL 4815; RO-0094815; Isavuconazole; trade name Cresemba.
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : 50~87 mg/mL ( 114.29~198.87 mM )
Ethanol : ~87 mg/mL |
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| 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. View More
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. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline |
| 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03149055 | COMPLETEDWITH RESULTS | Drug: Isavuconazole | Hematologic Malignancy Myeloproliferative Disorder |
Memorial Sloan Kettering Cancer Center | 2017-05-04 | Phase 2 |
| NCT01555918 | COMPLETED | Drug: Isavuconazole Drug: Isavuconazole |
Healthy Volunteers Pharmacokinetics of BAL4815 Pharmacokinetics of BAL8728 |
Astellas Pharma Inc | Phase 1 | |
| NCT04707703 | TERMINATED | Drug: Isavuconazonium Injection Drug: Placebo |
Aspergillosis Invasive Severe Acute Respiratory Syndrome Coronavirus 2 |
Jeffrey Jenks, MD, MPH | 2021-03-16 | Phase 3 |
| NCT01657890 | COMPLETED | Drug: isavuconazole | Healthy Volunteers Pharmacokinetics of Isavuconazole Safety and Tolerability in Elderly |
Astellas Pharma Global Development, Inc. | 2012-06 | Phase 1 |
| NCT01660477 | COMPLETED | Drug: Isavuconazole Drug: Lopinavir/ritonavir |
Healthy Volunteers Pharmacokinetics of Isavuconazole Pharmacokinetics of Lopinavir/Ritonavir |
Astellas Pharma Global Development, Inc. | 2012-06 | Phase 1 |
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