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Isavuconazonium | CAS No: 742049-41-8 | GMP-certified suppliers
A medication that treats invasive aspergillosis and mucormycosis in adult and pediatric patients with effective oral and intravenous antifungal therapy options.
Therapeutic categories
Primary indications
- 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
Product Snapshot
- Isavuconazonium is available as oral capsules and intravenous injectable formulations
- It is primarily used for the treatment of invasive aspergillosis and mucormycosis
- The drug is approved for use in major regulatory markets including the United States and Canada
Clinical Overview
Isavuconazonium is a water-soluble prodrug of isavuconazole, the active moiety. This prodrug formulation enhances solubility, facilitating both oral and intravenous administration. Unlike other intravenous azole antifungals such as voriconazole and posaconazole, isavuconazonium does not require a cyclodextrin solubilizing vehicle, thereby reducing the risk of nephrotoxicity associated with cyclodextrin exposure.
Pharmacodynamically, isavuconazole targets the fungal cytochrome P450 enzyme lanosterol 14-alpha-demethylase (Erg11p), inhibiting ergosterol synthesis, a critical component of the fungal cell membrane. This enzymatic inhibition disrupts membrane integrity and leads to fungal cell death. Selectivity is demonstrated by lower sensitivity of mammalian demethylation pathways to isavuconazole. Resistance mechanisms observed include mutations in the CYP51 gene, alterations in sterol composition, and increased efflux pump activity, with potential cross-resistance to other azoles, though clinical outcomes related to resistance remain to be fully elucidated.
Clinical trials indicate predictable pharmacokinetics with excellent oral bioavailability and a favorable safety profile. Isavuconazole exhibits dose-dependent shortening of the QTc interval, distinct from prolongation seen with other azoles; additive effects with other QTc-shortening agents are not established. Drug interaction potential includes inhibition and induction of several cytochrome P450 isoenzymes, notably CYP3A4.
Key ADME parameters reveal extensive metabolism primarily via CYP3A4, with elimination predominantly through fecal and urinary excretion. Monitoring is recommended in patients with significant hepatic impairment. Safety considerations emphasize avoidance in patients with known hypersensitivity, careful use in pediatric populations with approved indications, and awareness of potential drug-drug interactions due to cytochrome P450 modulation.
Isavuconazonium is commercially available under the brand name Cresemba, marketed by Astellas. For API procurement, attention should be given to the quality attributes ensuring consistent prodrug purity, solubility profiles, and compliance with regulatory standards. Robust characterization of the isavuconazonium sulfate salt form is critical, as is validation of manufacturing processes to mitigate residual impurities and ensure batch-to-batch consistency.
Identification & chemistry
| Generic name | Isavuconazonium |
|---|---|
| Molecule type | Small molecule |
| CAS | 742049-41-8 |
| UNII | VH2L779W8Q |
| DrugBank ID | DB06636 |
Pharmacology
| Summary | Isavuconazonium sulfate is a prodrug of isavuconazole, an azole antifungal targeting lanosterol 14-alpha-demethylase, a cytochrome P450 enzyme essential for ergosterol biosynthesis in fungal cell membranes. Inhibition of this enzyme disrupts ergosterol production, compromising membrane integrity and antifungal efficacy against invasive aspergillosis and mucormycosis. Resistance mechanisms may involve CYP51 gene mutations, altered sterol profiles, and efflux pump activity, with potential cross-resistance to other azoles. |
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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. |
| 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. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Lanosterol 14-alpha demethylase |
ADME / PK
| Absorption | 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) C<sub>max</sub> 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 (C<sub>max</sub>) 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 C<sub>max</sub> by 9% and increased AUC by 9%. isavuconazonium can be taken with or without food. |
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| Half-life | Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours. |
| Protein binding | Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin. |
| Metabolism | 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. |
| Route of elimination | 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. |
| Volume of distribution | Isavuconazole is extensively distributed with a mean steady-state volume of distribution (Vss) of approximately 450 L. |
| Clearance | 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). |
Formulation & handling
- Isavuconazonium is a small molecule API available for both oral (capsule) and intravenous (lyophilized powder) administration.
- Formulation stability considerations include protection from CYP3A4-modulating substances such as grapefruit and St. John's Wort during administration.
- Oral bioavailability is not significantly affected by food intake, allowing flexible dosing with regard to meals.
Regulatory status
| Lifecycle | The API is marketed in the US and Canada with key patent protections expiring between 2020 and 2028, indicating ongoing market exclusivity with gradual transition toward generic competition. |
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| Markets | Canada, US |
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Supply Chain
| Supply chain summary | Isavuconazonium is marketed primarily in North America, with branded products available in both the US and Canada. Multiple patents extend exclusivity in the United States through 2028, indicating limited generic competition currently but potential for entry following patent expirations. The supply landscape includes originator companies managing these patents and branded product distribution across these markets. |
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Safety
| Toxicity | Based on findings from animal studies, isavuconazonium may cause fetal harm when administered to a pregnant woman. There are no available human data on the use of isavuconazonium in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, perinatal mortality was increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at approximately 0.5 times the clinical exposure during pregnancy through the weaning period. In animal studies when isavuconazonium chloride was administered by oral gavage to pregnant rats and rabbits during organogenesis at exposures corresponding to less than the human maintenance dose increases in the incidences of multiple skeletal abnormalities, including rudimentary cervical ribs and fused zygomatic arches were observed. During clinical studies, total daily isavuconazonium doses higher than the recommended dose regimen were associated with an increased rate of adverse reactions. At supratherapeutic doses (three times the recommended maintenance dose) evaluated in a thorough QT study, there were proportionally more treatment-emergent adverse reactions than in the therapeutic dose group (maintenance dose) for the following: headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. Adverse reactions leading to discontinuation of the study drug occurred in 7 of 39 (17.9%) subjects in the supratherapeutic dose group. Isavuconazole is not removed by hemodialysis. There is no specific antidote for isavuconazole. Treatment should be supportive with appropriate monitoring. In a 2-year rat carcinogenicity study and a 2-year mouse carcinogenicity study, dose-related increases in hepatocellular adenomas and/or carcinomas were observed in male and female B6C3F1/Crl mice and male, but not female Han Wistar rats at doses as low as 0.1 times the exposure seen in humans administered the maintenance dose. Hepatic hemangiomas were increased in female mice at 300 mg/kg, at an exposure similar to the maintenance dose. Hepatoblastoma was increased in male mice at 100 mg/kg, about 0.4 times the systemic exposures based on AUC comparisons. Thyroid follicular cell adenomas were observed in male and female rats at doses as low as 60 mg/kg in male rats (about 0.2 times the human clinical maintenance dose). The relevance of rat thyroid tumors to human carcinogenic risk remains unclear. A significant increase in the incidence of skin fibromas was seen in male rats at 300 mg/kg, exposures 0.8 times the human exposure at the human clinical maintenance dose. Uterine adenocarcinomas were observed in female rats at 200 mg/kg, at systemic exposures similar to the human exposure at the human clinical maintenance dose. No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats. Oral administration of isavuconazonium sulfate did not affect fertility in male or female rats treated at doses up to 90 mg/kg/day (approximately 0.3 times the systemic exposure at the human clinical maintenance dose). |
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- Animal studies indicate isavuconazonium may cause fetal harm, including increased perinatal mortality and skeletal abnormalities, at exposures below or near human clinical doses
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Isavuconazonium is a type of Antimycotics
Antimycotics, a subcategory of pharmaceutical Active Pharmaceutical Ingredients (APIs), are essential in the treatment of various fungal infections. These powerful medications target and eliminate harmful fungi that can cause infections in humans.
Antimycotics are classified into two main types: systemic and topical. Systemic antimycotics are administered orally or intravenously and work by circulating throughout the body, treating systemic fungal infections that affect internal organs or spread throughout the bloodstream. On the other hand, topical antimycotics are applied externally to treat localized fungal infections such as athlete's foot or yeast infections.
The efficacy of antimycotics lies in their ability to disrupt fungal cell membranes, inhibit the synthesis of fungal DNA or proteins, or interfere with essential metabolic processes specific to fungi. This targeted action minimizes damage to human cells, making these medications relatively safe for patients.
Commonly prescribed antimycotics include azoles, polyenes, allylamines, and echinocandins. Azoles inhibit the synthesis of ergosterol, a vital component of fungal cell membranes, while polyenes bind to ergosterol, resulting in the formation of pores that lead to cell death. Allylamines disrupt the synthesis of ergosterol and inhibit the activity of squalene epoxidase, an enzyme involved in ergosterol production. Echinocandins target the synthesis of β-(1,3)-D-glucan, an essential component of the fungal cell wall.
Antimycotics play a crucial role in the management of fungal infections, offering relief to patients and aiding in their recovery. As with any medication, it is important to follow healthcare professionals' guidance regarding dosage, duration of treatment, and potential side effects to ensure optimal therapeutic outcomes.
Isavuconazonium (Antimycotics), classified under Antifungals
Antifungals are a vital category of pharmaceutical active pharmaceutical ingredients (APIs) designed to combat fungal infections. These medications are developed to target and eliminate fungi, including yeasts and molds, which can cause a range of diseases in humans and animals.
Antifungals work by interfering with specific components or processes essential for fungal growth and reproduction. They may inhibit the synthesis of fungal cell walls or disrupt the production of ergosterol, a crucial component of fungal cell membranes. By targeting these key mechanisms, antifungal APIs effectively hinder the growth and spread of fungal infections.
The diversity within the antifungal category is reflected in the various classes of antifungal APIs available. Azoles, polyenes, echinocandins, and allylamines are common classes of antifungals. Each class exhibits unique mechanisms of action and targets specific types of fungi. This diversity enables healthcare professionals to tailor treatment plans to the specific fungal infection, optimizing therapeutic outcomes.
Antifungal APIs find application in various pharmaceutical formulations, including oral medications, topical creams, ointments, and intravenous solutions. They are crucial for the treatment of common fungal infections like athlete's foot, ringworm, vaginal yeast infections, and oral thrush. Additionally, antifungals play a crucial role in managing serious systemic fungal infections that can pose significant health risks, especially in immunocompromised individuals.
Overall, antifungal APIs are indispensable tools in the fight against fungal infections, offering effective treatment options and improving the quality of life for patients suffering from these conditions. With ongoing research and development, the antifungal category continues to evolve, providing innovative solutions to combat the ever-changing landscape of fungal pathogens.
Isavuconazonium API manufacturers & distributors
Compare qualified Isavuconazonium API suppliers worldwide. We currently have 3 companies offering Isavuconazonium API, with manufacturing taking place in 3 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| ACE Japan | Producer | Japan | Japan | CoA | 76 products |
| Apino Pharma Co., Ltd. | Producer | China | China | BSE/TSE, CoA, GMP, USDMF | 229 products |
| Global Pharma Tek | Distributor | India | India | BSE/TSE, CoA, FDA, GMP, ISO9001, MSDS | 484 products |
When sending a request, specify which Isavuconazonium API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
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