Absorption, Distribution and Excretion
In healthy subjects, the pharmacokinetics of ixaconazole following oral administration of ixaconazole capsules (equivalent to 600 mg of ixaconazole daily, i.e., 6 capsules) were dose-proportional. In 66 fasting healthy male subjects, the mean (standard deviation) Cmax and AUC after oral administration of ixaconazole capsules equivalent to 200 mg of ixaconazole, followed by a single dose of two 186 mg ixaconazole capsules and five 74.5 mg ixaconazole capsules, were 3.3 (0.6) mg/L and 112.2 (30.3) mg·hr/L, and 3.3 (0.6) mg/L and 118.0 (33.1) mg·hr/L, respectively. In healthy volunteers, the active ingredient ixaconazole typically reaches its maximum plasma concentration (Cmax) 2 to 3 hours after single or multiple administrations. Following oral administration, the absolute bioavailability of ixaconazole is 98%. No significant concentrations of prodrug or inactive cleavage products were detected in plasma after oral administration. Following intravenous administration of ixaconazole, the maximum plasma concentrations of prodrug and inactive cleavage products were detectable during infusion and rapidly decreased after administration. Prodrug concentrations were below the limit of detection 1.25 hours after the start of the 1-hour infusion. The total prodrug exposure, calculated based on AUC, was less than 1% of ixaconazole. In some subjects, inactive cleavage products remained detectable up to 8 hours after the start of infusion. The total exposure to inactive cleavage products, based on AUC, was approximately 1.3% of ixaconazole. Intravenous infusion of ixaconazole solution via nasogastric tube provides similar systemic ixaconazole exposure as oral capsules. Concomitant administration of the equivalent of a 400 mg oral dose of ixaconazole with a high-fat meal decreased the Cmax of ixaconazole by 9% and increased the AUC by 9%. Ixaconazole can be taken on an empty stomach or with food.
After oral administration of radiolabeled ixaconazole sulfate to healthy volunteers, an average of 46.1% of the total radioactive dose was recovered in feces and 45.5% in urine. Less than 1% of the administered dose is excreted renally from ixaconazole itself. Inactive cleavage products are primarily eliminated through metabolism and renal excretion of their metabolites. Less than 1% of the total administered dose is excreted renally from intact cleavage products. Following intravenous administration of radiolabeled cleavage products, 95% of the total radioactive dose is excreted in urine.
Ixaconazole is widely distributed, with a mean steady-state volume of distribution (Vss) of approximately 450 L.
In healthy subjects, the clearance of ixaconazole is estimated to be 2.4 to 4.1 L/h. Studies have found that the mean clearance in Chinese subjects was 40% lower than in Western subjects (1.6 L/hr in Chinese subjects vs. 2.6 L/hr in Western subjects).

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Metabolism/Metabolites
In vitro studies have shown that isosaconazole sulfate is rapidly hydrolyzed in the blood by esterases (primarily butylcholinesterase) to isosaconazole. Isosaconazole is a substrate of cytochrome P450 enzymes 3A4 and 3A5. Following single administration of [cyano-14C]isosaconazole and [pyridinemethyl-14C]isosaconazole in humans, several minor metabolites were identified in addition to the active ingredient (isosaconazole) and inactive cleavage products. No single metabolite other than the active ingredient isosaconazole was observed to have an AUC exceeding 10% of drug-related substances. In vivo studies have shown that CYP3A4, CYP3A5, and subsequently uridine diphosphate glucuronide transferase (UGT) are involved in the metabolism of isosaconazole.

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Biological Half-Life
Based on population pharmacokinetic analysis of healthy subjects and patients, the mean plasma half-life of ixaconazole is 130 hours.

Hepatotoxicity
In patients taking ixaconazole, 1% to 5% experience transient increases in serum transaminase levels. These increases are usually asymptomatic and resolve spontaneously, but a small number of patients require discontinuation of ixaconazole due to elevated ALT. Clinically significant hepatotoxicity has not been reported with ixaconazole, but its use is limited. Other triazoles, such as fluconazole and voriconazole, have been marketed and widely used for over a decade, but are associated with rare cases of clinically significant liver injury. This injury usually occurs within the first few months of treatment, with serum enzyme elevations ranging from cholestatic to hepatocellular. Several cases of acute liver failure caused by other triazoles have been reported. Immune allergic reactions and autoantibodies are uncommon. Recovery typically takes 6 to 10 weeks after discontinuation of treatment, but in some cases, full recovery may take longer. Probability score: E (Unproven but suspected cause of clinically significant liver injury).

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Protein binding
Isavuconazonium is highly bound to proteins (greater than 99%), primarily 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, the cationic moiety of ixaconazole sulfate (an antifungal drug used to treat invasive aspergillosis and invasive mucormycosis, and a prodrug of ixaconazole). It has multiple functions, including as a prodrug, an inhibitor of ergosterol biosynthesis, an EC 1.14.13.70 (sterol 14α-demethylase) inhibitor, and an antifungal agent. Isavuconazonium is a second-generation triazole antifungal drug, approved by the U.S. Food and Drug Administration (FDA) on March 6, 2015, and by the European Medicines Agency (EMA) in July 2015, for the treatment of invasive aspergillosis and invasive mucormycosis in adults. It is marketed by Astellas Pharma under the brand name Cresemba. It is a prodrug form of the active ingredient, ixaconazole, and is available in both oral and injectable formulations. Due to the low solubility of ixaconazole itself in water, isoxaconazole ammonium formulations are preferred because of their high water solubility and ability to be administered intravenously. This formulation also avoids the use of cyclodextrin as a solubilizer (a solvent required for intravenous administration of other antifungal drugs such as voriconazole and posaconazole), thus eliminating the risk of cyclodextrin-related nephrotoxicity. Isavuconazonium ammonium has excellent oral bioavailability, predictable pharmacokinetics, and a favorable safety profile, making it a reasonable alternative to the few other drugs in its class on the market. On December 8, 2023, the FDA approved the expanded use of isoxaconazole ammonium in pediatric patients, with the same indications as the aforementioned drugs. Isavuconazonium ammonium is a triazole antifungal drug primarily used to treat invasive aspergillosis and mucormycosis infections. The incidence of transient and asymptomatic elevations of serum transaminases during isoxaconazole treatment is low, but no clinically significant cases of acute drug-induced liver injury have been found.

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Drug Indications
Isavuconazonium is indicated for the treatment of invasive aspergillosis and mucormycosis in adults and children aged 1 year and older. Capsules are indicated for the treatment of invasive aspergillosis and mucormycosis in adults and children aged 6 years and older weighing 16 kg or more. Injections are indicated for the treatment of invasive aspergillosis and mucormycosis in adults and children weighing 16 kg or more.
FDA Label

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Mechanism of Action
Isavuconazonium sulfate is a prodrug of the azole antifungal drug ixaconazole. Isavuconazonium inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, by inhibiting the cytochrome P-450-dependent enzyme lanosterol 14-α-demethylase (Erg11p). This enzyme is responsible for converting lanosterol to ergosterol. The accumulation of methylated sterol precursors and the depletion of ergosterol within the fungal cell membrane weaken the cell membrane's structure and function. Demethylation in mammalian cells is less sensitive to the inhibitory effect of ixaconazole.

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Pharmacodynamics
In a controlled trial, no significant correlation was found between plasma AUC or plasma itaconazole concentration and efficacy in patients receiving itaconazole for invasive aspergillosis. The study also evaluated the effect of repeated doses of itaconazole capsules on the QTc interval. In a randomized, placebo- and active-controlled (moxifloxacin 400 mg single dose), quadruple-group parallel treatment study, 160 healthy subjects received itaconazole treatment. On days 1 and 2, subjects took two itaconazole capsules (equivalent to 200 mg of itaconazole) three times daily, followed by 2 or 6 itaconazole capsules (equivalent to 600 mg of itaconazole) once daily for 13 consecutive days. Results showed that itaconazole caused a dose-dependent shortening of the QTc interval.
For the 2-capsule dosing regimen, the least squares mean (LSM) difference in QTc interval compared to placebo was -13.1 ms at 2 hours post-dose [90% CI: -17.1, -9.1 ms]. Increasing the dose to 6 capsules resulted in a LSM difference of -24.6 ms compared to placebo at 2 hours post-dose [90% confidence interval: -28.7, -20.4]. Isavuconazonium has not been evaluated for co-administration with other drugs that shorten the QTc interval, therefore its additive effect is unclear. Like other azole antifungals, ixaconazole resistance mechanisms likely involve multiple mechanisms, including amino acid substitutions in the target gene CYP51. Changes in the sterol profile and increased efflux pump activity have been observed; however, the clinical significance of these findings is unclear. In vitro and animal studies have demonstrated cross-resistance between ixaconazole and other azole drugs. The correlation between cross-resistance and clinical outcomes is not fully understood; however, patients who have failed prior azole therapy may require alternative antifungal treatments.

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.)