Absorption, Distribution and Excretion
In healthy subjects, the pharmacokinetics of isavuconazole following oral administration of isavuconazonium capsules at isavuconazole equivalent doses up to 600 mg per day (6 capsules) are dose-proportional. Following oral administration of isavuconazonium capsules at an isavuconazole equivalent dose of 200 mg in 66 fasted healthy male subjects, a single dose administration of two 186 mg isavuconazonium capsules and five 74.5 mg isavuconazonium capsules exhibited a mean (SD) Cmax and AUC of 3.3 (0.6) mg/L and 112.2 (30.3) mg·hr/L, respectively, and 3.3 (0.6) mg/L and 118.0 (33.1) mg·hr/L, respectively. After oral administration of isavuconazonium in healthy volunteers, the active moiety, isavuconazole, generally reaches maximum plasma concentrations (Cmax) 2 hours to 3 hours after single and multiple dosing. The absolute bioavailability of isavuconazole following oral administration of isavuconazonium is 98%. No significant concentrations of the prodrug or inactive cleavage product were seen in plasma after oral administration. Following intravenous administration of isavuconazonium, maximal plasma concentrations of the prodrug and inactive cleavage product were detectable during infusion and declined rapidly following the end of administration. The prodrug was below the level of detection by 1.25 hours after the start of a one-hour infusion. The total exposure of the prodrug based on AUC was less than 1% that of isavuconazole. The inactive cleavage product was quantifiable in some subjects up to 8 hours after the start of infusion. The total exposure of inactive cleavage product based on AUC was approximately 1.3% that of isavuconazole. Isavuconazonium given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule. Coadministration of isavuconazonium equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole Cmax by 9% and increased AUC by 9%. isavuconazonium can be taken with or without food.
Following oral administration of radio-labeled isavuconazonium sulfate to healthy volunteers, a mean of 46.1% of the total radioactive dose was recovered in the feces and 45.5% was recovered in the urine. Renal excretion of isavuconazole itself was less than 1% of the dose administered. The inactive cleavage product is primarily eliminated by metabolism and subsequent renal excretion of the metabolites. Renal elimination of intact cleavage product was less than 1% of the total dose administered. Following intravenous administration of radio-labeled cleavage product, 95% of the total radioactive dose was excreted in the urine.
Isavuconazole is extensively distributed with a mean steady-state volume of distribution (Vss) of approximately 450 L.
In healthy subjects, the clearance of isavuconazole was estimated to be from 2.4 to 4.1 L/h. Chinese subjects were found to have on average a 40% lower clearance compared to Western subjects (1.6 L/hr for Chinese subjects as compared to 2.6 L/hr for Western subjects).

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Metabolism / Metabolites
In in vitro studies, isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases, predominantly by butylcholinesterase. Isavuconazole is a substrate of cytochrome P450 enzymes 3A4 and 3A5. Following single doses of [cyano 14C] isavuconazonium and [pyridinylmethyl 14C] isavuconazonium in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, several minor metabolites were identified. Except for the active moiety isavuconazole, no individual metabolite was observed with an AUC greater than 10% of drug-related material. In vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole.

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Biological Half-Life
Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours.

Hepatotoxicity
Transient elevations in serum aminotransferase levels occur in 1% to 5% of patients on isavuconazonium. These elevations are usually asymptomatic and self-limited, but occasional patients require discontinuation of isavuconazonium because of ALT elevations. Clinically apparent hepatotoxicity has not been reported with isavuconazonium, but it has had limited general use. Other triazoles, such as fluconazole and voriconazole that have been available for more than a decade and have had wide scale use, have been associated with rare instances of clinically apparent liver injury. The injury arises within the first few months of therapy and the pattern of serum enzyme elevations has been variable from cholestatic to hepatocellular. Several cases of acute liver failure attributed to other triazoles have been reported. Immunoallergic features and autoantibodies are uncommon. Recovery upon stopping therapy generally takes 6 to 10 weeks but, in some cases, the time to complete resolution may be prolonged.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

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Protein Binding
Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin.

1: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. Isavuconazonium. 2018 Apr 27. PMID: 31643955. 2: McCormack PL. Isavuconazonium: first global approval. Drugs. 2015 May;75(7):817-22. doi: 10.1007/s40265-015-0398-6. PMID: 25902926. 3: Walker RC, Zeuli JD, Temesgen Z. Isavuconazonium sulfate for the treatment of fungal infection. Drugs Today (Barc). 2016 Jan;52(1):7-16. doi: 10.1358/dot.2016.52.1.2404002. PMID: 26937491. 4: Isavuconazonium sulfate (Cresemba)--a new antifungal. Med Lett Drugs Ther. 2016 Mar 14;58(1490):37-8. PMID: 26963156. 5: McCreary EK, Nguyen MH, Davis MR, Borlagdan J, Shields RK, Anderson AD, Rivosecchi RM, Marini RV, Sacha LM, Silveira FP, Andes DR, Lepak AJ. Achievement of clinical isavuconazole blood concentrations in transplant recipients with isavuconazonium sulphate capsules administered via enteral feeding tube. J Antimicrob Chemother. 2020 Oct 1;75(10):3023-3028. doi: 10.1093/jac/dkaa274. PMID: 32710097; PMCID: PMC7778376. 6: Murrell D, Bossaer JB, Carico R, Harirforoosh S, Cluck D. Isavuconazonium sulfate: a triazole prodrug for invasive fungal infections. Int J Pharm Pract. 2017 Feb;25(1):18-30. doi: 10.1111/ijpp.12302. Epub 2016 Aug 29. PMID: 27569742. 7: Adamsick ML, Elshaboury RH, Gift T, Mansour MK, Kotton CN, Gandhi RG. Therapeutic drug concentrations of isavuconazole following the administration of isavuconazonium sulfate capsules via gastro-jejunum tube: A case report. Transpl Infect Dis. 2019 Apr;21(2):e13048. doi: 10.1111/tid.13048. Epub 2019 Jan 29. PMID: 30636363. 8: Peyton LR, Gallagher S, Hashemzadeh M. Triazole antifungals: a review. Drugs Today (Barc). 2015 Dec;51(12):705-18. doi: 10.1358/dot.2015.51.12.2421058. PMID: 26798851. 9: Kovanda LL, Maher R, Hope WW. Isavuconazonium sulfate: a new agent for the treatment of invasive aspergillosis and invasive mucormycosis. Expert Rev Clin Pharmacol. 2016 Jul;9(7):887-97. doi: 10.1080/17512433.2016.1185361. Epub 2016 May 21. PMID: 27160418. 10: Reid G, Lynch JP 3rd, Fishbein MC, Clark NM. Mucormycosis. Semin Respir Crit Care Med. 2020 Feb;41(1):99-114. doi: 10.1055/s-0039-3401992. Epub 2020 Jan 30. PMID: 32000287.

Isavuconazonium is an organic cation that is the cationic portion of isavuconazonium sulfate (a prodrug for isavuconazole, an antifungal agent used for the treatment of invasive aspergillosis and invasive mucormycosis). It has a role as a prodrug, an ergosterol biosynthesis inhibitor, an EC 1.14.13.70 (sterol 14alpha-demethylase) inhibitor and an antifungal agent.
Isavuconazonium is a second-generation triazole antifungal approved on March 6, 2015 by the FDA and July 2015 by the EMA for the treatment of adults with 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. On December 08, 2023, the FDA approved the expanded use of isovuconazonium in pediatric patients for the same indications.
Isavuconazonium is a triazole antifungal agent used primarily in the treatment of invasive aspergillosis and mucormycosis infections. Isavuconazonium is associated with a low rate of transient and asymptomatic serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent acute drug induced liver injury.

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Drug Indication
Isavuconazonium is indicated for the treatment of invasive aspergillosis and mucormycosis in adults and pediatric patients 1 year of age and older in capsule form and adults and pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater in injection form.
FDA Label

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Mechanism of Action
Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal. Isavuconazole inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, by inhibiting cytochrome P-450-dependent enzyme lanosterol 14-alpha-demethylase (Erg11p). This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weaken the membrane structure and function. Mammalian cell demethylation is less sensitive to isavuconazole inhibition.

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Pharmacodynamics
In patients treated with isavuconazonium for invasive aspergillosis in a controlled trial, there was no significant association between plasma AUC or plasma isavuconazole concentration and efficacy. The effect on QTc interval of multiple doses of isavuconazonium capsules was evaluated. Isavuconazonium was administered as 2 capsules (equivalent to 200 mg isavuconazole) three times daily on days 1 and 2 followed by either 2 capsules or 6 capsules (equivalent to 600 mg isavuconazole) once daily for 13 days in a randomized, placebo- and active-controlled (moxifloxacin 400 mg single-dose), four-treatment-arms, parallel study in 160 healthy subjects. Isavuconazole resulted in dose-related shortening of the QTc interval. For the 2-capsule dosing regimen, the least squares mean (LSM) difference from placebo was -13.1 msec at 2 hours postdose [90% CI: -17.1, -9.1 msec]. Increasing the dose to 6 capsules resulted in an LSM difference from the placebo of -24.6 msec at 2 hours postdose [90% CI: -28.7, -20.4]. Isavuconazonium was not evaluated in combination with other drugs that reduce the QTc interval, so the additive effects are not known. The mechanism of resistance to isavuconazole, like other azole antifungals, is likely due to multiple mechanisms that include substitutions in the target gene CYP51. Changes in sterol profile and elevated efflux pump activity were observed; however, the clinical relevance of these findings is unclear. In vitro and animal studies suggest cross-resistance between isavuconazole and other azoles. The relevance of cross-resistance to clinical outcomes has not been fully characterized; however, patients failing prior azole therapy may require alternative antifungal therapy.

C35H37F2N8O5S+

719.78

717.242

C, 58.40; H, 5.18; F, 5.28; N, 15.57; O, 11.11; S, 4.45

742049-41-8

338990-84-4 (chloride);497235-79-7 (chloride HCl);742049-41-8 (cation);946075-13-4 (sulfate);

6918606

Solid powder

4.975

2

13

15

51

1210

2

S1C=C(C2C=CC(C#N)=CC=2)N=C1[C@H](C)[C@@](C1C=C(C=CC=1F)F)(CN1C=[N+](C=N1)C(C)OC(N(C)C1C(=CC=CN=1)COC(CNC)=O)=O)O

AWANULZDKHTBBZ-QXLBVTBOSA-O

InChI=1S/C35H36F2N8O5S/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/h5-14,18,20,22-23,39,48H,16-17,19,21H2,1-4H3/p+1/t22-,23?,35+/m0/s1

Glycine, N-methyl-, (2-(((1-(1-((2R,3R)-3-(4-(4-cyanophenyl)-2-thiazolyl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-1H-1,2,4-triazolium-4-yl)ethoxy)carbonyl)methylamino)-3-pyridinyl)methyl ester

Isavuconazonium Free Base; BAL8557; BAL 8557; BAL-8557

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)