CYP3
Azole antifungal agent (triazole) [1]

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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Isavuconazole exhibited potent in vitro activity against 296 clinical Candida bloodstream isolates collected between 1995 and 2004. The MIC50 for all isolates was 0.004 mg/L, with MIC50/MIC90 values ranging from ≤0.002/0.004 mg/L for C. albicans to 0.25/0.5 mg/L for C. glabrata.
It was more active (lower MIC50) than amphotericin B (0.5 mg/L), itraconazole (0.008 mg/L), voriconazole (0.03 mg/L), flucytosine (0.125 mg/L), and fluconazole (8 mg/L).
Only two C. glabrata isolates showed MICs >0.5 mg/L (2 and 4 mg/L), while all other isolates, including fluconazole-resistant strains, were highly susceptible. [1]

Animal models (primarily murine) have been used for dose-finding experiments and efficacy assessments. The area under the curve to MIC ratio (AUC/MIC) is the primary predictor of drug efficacy in murine models of invasive pulmonary aspergillosis. Studies in immunosuppressed murine models of mucormycosis showed that isavuconazole therapy protects mice from infection. Efficacy has also been evaluated in models of disseminated candidiasis and cryptococcal meningitis. [3]

Broth microdilution susceptibility testing was performed according to CLSI (formerly NCCLS) guideline M27-A2. RPMI 1640 medium buffered with MOPS to pH 7.0 was used. The final inoculum concentration was 0.5×10³ to 2.5×10³ cells/mL.
Microtiter plates containing dehydrated antifungal agents were incubated at 35°C for 24–48 hours. MICs were determined visually: for amphotericin B as the lowest concentration with no growth, and for azoles and flucytosine as the lowest concentration causing a ≥50% reduction in growth compared to the drug-free control.
Quality control strains C. parapsilosis ATCC 22019 and C. krusei ATCC 6258 were used. [1]

Animal studies are described in general terms. Murine models of invasive fungal infections (e.g., invasive pulmonary aspergillosis, disseminated candidiasis, mucormycosis) are established in immunocompromised mice. The animals are infected with specific fungal strains (e.g., Aspergillus fumigatus). Isavuconazole is administered via specified routes (implied intravenously or orally, based on the active moiety from its prodrug), typically following a loading dose regimen to achieve steady-state levels rapidly. Efficacy endpoints include survival rates, fungal burden in target organs (e.g., kidneys, lungs), and histopathological analysis. [3]

Absorption, Distribution and Excretion
Following oral administration of 200 mg Isavuconazonium, the mean steady-state peak plasma concentration (Cmax) was 7499 ng/mL. After oral administration of 600 mg Isavuconazonium, the Cmax was 20028 ng/mL. It is estimated that the steady-state Cmax is reached approximately 2–3 hours after a single or multiple doses of Isavuconazonium. After oral and intravenous administration of 400 mg Isavuconazonium, the mean AUCs were 189462.8 hng/mL and 193906.8 hng/mL, respectively. Isavuconazonium can be taken with or without food, but the intake of high-fat foods concurrently reduces the Cmax of oral Isavuconazonium by 9% and increases the AUC by 9%. The absolute bioavailability of Isavuconazonium after a single oral dose is 98%. Following oral administration, 46.1% of the radiolabeled Isavuconazonium was detected in feces, and approximately 45.5% was recovered in urine. The amount of unmetabolized ixaconazole in urine is less than 1% of the total administered dose. The mean steady-state volume of distribution (Vss) after intravenous administration is approximately 450 L. The clearance (CL) of 200 mg ixaconazole administered orally or intravenously is 2.5 ± 1.6 L/h. Metabolites: Following the rapid esterase-mediated hydrolysis of the prodrug ixaconazole to ixaconazole, several minor metabolites were identified, in addition to the active moiety and its inactive cleavage products. However, no single metabolite was observed to have an AUC exceeding 10% of the total radiolabeled material. Based on in vivo and in vitro studies, the major enzymes involved in the metabolism of ixaconazole are CYP3A4, CYP3A5, and subsequently uridine diphosphate glucuronide transferase (UGT). Biological half-life: Based on population pharmacokinetic analysis in healthy subjects and patients, the mean plasma half-life of ixaconazole is 130 hours. The mean half-lives after oral and intravenous administration of 400 mg ixaconazole were 110 hours and 115 hours, respectively. The prodrug ixaconazole sulfate is rapidly hydrolyzed in plasma primarily by serum butylcholinesterase to the active antifungal drug ixaconazole and an inactive cleavage product. Neither the prodrug nor its cleavage product is detectable within 30 minutes after intravenous infusion or 2–3 hours after oral administration. The pharmacokinetics of ixaconazole are linear dose-proportional with low inter-patient variability (one study reported a steady-state concentration of 2.5 ± 1.0 μg/mL). Its oral bioavailability is excellent (approximately 98%) and is unaffected by food. It has a large volume of distribution (approximately 450 L), indicating its wide tissue distribution. The terminal half-life is approximately 130 hours. It is primarily eliminated via hepatic metabolism, with fecal excretion being the main route of elimination; renal excretion is less than 1% of the administered dose. Metabolism involves CYP3A4, CYP3A5, and uridine diphosphate glucuronide transferase (UGT). No dose adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh A or B) or renal impairment. Data for severe hepatic impairment (Child-Pugh C) are insufficient. Although this drug may not be cleared by hemodialysis, pharmacokinetic studies have not been conducted in dialysis patients. [3]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information on the clinical use of ixaconazole during lactation. Because ixaconazole binds to plasma proteins at a rate exceeding 99%, its concentration in breast milk may be very low. However, there is currently no published experience regarding the use of ixaconazole during lactation; therefore, especially in breastfeeding newborns or premature infants, alternative medications may be preferred.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
Isavuconazonium has a high protein binding rate (greater than 99%), primarily binding to albumin.

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Isavuconazonium is generally well tolerated. In the SECURE study, ixacinazole significantly reduced drug-related adverse events (42.4%) compared to voriconazole (59.8%). Less common adverse events with ixacinazole include visual disturbances, elevated liver enzymes, and photosensitivity. Reported side effects include hypokalemia, peripheral edema, infusion-related reactions (e.g., acute respiratory distress, chills, dyspnea, hypotension), and gastrointestinal discomfort (nausea, vomiting, diarrhea). It has a unique dose- and concentration-dependent QT interval shortening effect (to 13 ms with 200 mg daily and 24.6 ms with 600 mg daily in healthy volunteers). It is contraindicated in patients with familial short QT syndrome. Ixacinazole is a moderate inhibitor of CYP3A4 and may lead to elevated plasma concentrations of drugs metabolized by this enzyme (e.g., sirolimus, tacrolimus, and cyclosporine) when taken concurrently, thus requiring therapeutic drug monitoring for these drugs. It should be avoided when used concurrently with potent CYP3A4 inducers (e.g., rifampin, carbamazepine). It is a pregnancy category C drug and will pass into breast milk. To date, no long-term side effects associated with voriconazole, such as skin malignancies and high fluoride poisoning/periodontitis, have been observed. [3]

[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.

Pharmacodynamics
Isavuconazonium exhibits antifungal activity against most Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, and Mucorales fungi (such as Rhizopus oryzae and Mucor). In a cardiac electrophysiology study involving healthy subjects, ixaconazole caused a dose-dependent shortening of the QTc interval, but the additive effect of ixaconazole with other QTc prolonging drugs is unclear. Isavuconazonium is the active ingredient of the prodrug BAL8557, a water-soluble triazole prodrug suitable for oral and intravenous administration. It has broad-spectrum in vitro activity against a variety of major opportunistic fungi, including Candida, Cryptococcus, Aspergillus, Rhizopus, Mucor, and type II fungi. Currently, ixaconazole is in Phase III clinical development and is expected to be used to treat systemic Candida infections, including those caused by fluconazole-resistant strains. [1]

C22H17F2N5OS

437.4651

437.112

C, 60.40; H, 3.92; F, 8.69; N, 16.01; O, 3.66; S, 7.33

241479-67-4

Isavuconazole-d4;1346598-58-0

6918485

Solid powder

1.38

678ºC at 760 mmHg

363.8ºC

4.242

1

8

6

31

657

2

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]

DDFOUSQFMYRUQK-RCDICMHDSA-N

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

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

BAL4815; RO0094815; BAL-4815; RO 0094815; BAL 4815; RO-0094815; Isavuconazole; trade name Cresemba.

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)

DMSO : 50~87 mg/mL ( 114.29~198.87 mM )
Ethanol : ~87 mg/mL

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.

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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.

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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.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline

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