241479-67-4 Usage
Description
Isavuconazole, also known as BAL-4815, is a water-soluble pro-drug of BAL-8557 (isavuconazonium). It is a new triazole antifungal drug developed by Basilea Pharmaceutica. Isavuconazole works by inhibiting ergosterol synthesis, which is essential for the growth and integrity of fungal cell membranes. It is a broad-spectrum antifungal agent with oral and intravenous formulations, excellent bioavailability, and a long elimination half-life that allows for up to once-weekly dosing.
Uses
Used in Pharmaceutical Industry:
Isavuconazole is used as an antifungal agent for the treatment of invasive aspergillosis and invasive mucormycosis. It has shown in vitro activity against a large number of clinically important yeasts and molds, including Aspergillus spp., Fusarium spp., Scedosporium spp., Candida spp., the Zygomycetes, and Cryptococcus spp. This makes it a promising candidate for the treatment of various fungal infections, particularly those caused by drug-resistant strains.
Used in Clinical Trials:
Isavuconazole is currently undergoing phase III clinical trials, which are essential for evaluating its safety, efficacy, and optimal dosing regimens in treating invasive fungal infections. The results of these trials will help determine the potential role of isavuconazole in the management of these infections and its place in the antifungal drug market.
Used in Drug Resistance Management:
Due to its broad-spectrum activity and unique mechanism of action, isavuconazole has the potential to be used in the management of drug-resistant fungal infections. This could be particularly beneficial in cases where traditional antifungal agents have failed or are contraindicated.
Used in Combination Therapy:
Isavuconazole may also be used in combination with other antifungal agents to enhance the treatment of invasive fungal infections. This could help improve the overall efficacy of the treatment and reduce the likelihood of drug resistance development.
Antimicrobial activity
Isavuconazole is a new broad-spectrum triazole with activity against Candida, Cryptococcus, Aspergillus, Zygomycetes, Rhizopus, and Rhizomucor spp. and dimorphic fungi including Histoplasma capsulatum and Blastomyces dermatitidis and a range of dermatophytes. In animal models, isavuconazole is highly effective against systemic candidiasis and disseminated Aspergillus fumigatus and flavus infections.
Biochem/physiol Actions
Maximum plasma concentrations of BAL 4815 are observed 1.5–3 hours after oral doses or at the end of the 1-hour intravenous infusion. Mean elimination half-lives are remarkably long more than 50 and 70 hours after oral and intravenous doses, respectively, allowing for once-daily (or less frequent) dosing. The volume of distribution is large and systemic clearance low. The protein binding is 98%. Escalation in multiple dosing regimens results in a proportional increase in maximum plasma drug concentration.
Clinical Use
Three regimens of isavuconazonium (BAL 8557) – single 200 mg dose followed by 50 mg daily, single 400 mg followed by 100 mg daily and single 400 mg followed by 400 mg weekly –were demonstrated to be as efficacious as fluconazole in a phase II study conducted on patients with uncomplicated esophageal candidiasis. The results of a phase II open-label dose-escalating trial of intravenous isavuconazonium as prophylaxis in AML (NCT00413439) are pending (NIH, 2008). Two phase III randomized double-blind studies to evaluate the safety and efficacy of isavuconazole are currently under way, versus caspofungin followed by voriconazole in the treatment of candidaemia and invasive candidiasis and versus voriconazole in primary treatment of invasive filamentous fungal infection . A phase III open-label study using isavuconazole in patients with aspergillosis and renal impairment and those with rare fungi is being planned NCT00634049.
Toxicology
In animals, isavuconazole has revealed no mutagenic, allergenic,
phototoxic, or irritant potential. In
15 healthy volunteers, single doses of isavuconazole (up to 200 mg)
were well tolerated, and no severe or serious adverse events occurred. In a multiple-dose pharmacokinetic
study, 24 healthy males received isavuconazole for 21 days of oral or
14 days of intravenous dosing. The
most frequent adverse events were headache, nasopharyngitis, and
rhinitis, and all were mild or moderate; however one subject on oral
high-dose BAL 8557 had mild transient abnormal liver function on day
14 of therapy, which resolved despite continuing the drug. No clinically relevant changes in vital signs or
electrocardiogram were observed. In a double-blind randomized phase
II trial for the treatment of esophageal candidiasis, BAL 8557 was safe
and well tolerated, with an adverse event profile similar to that of
fluconazole, the comparator drug.
Drug interactions
Rifampicin, a potent CYP3A4 inducer, decreases the Cmax and AUC
of isavuconazole . Ketoconazole
increases exposure to isavuconazole.
Neither ciclosporin nor warfarin is affected by isavuconazole co-administration. Isavuconazole increases tacrolimus levels.
Metabolism
Molecular weight (daltons) 814.8 (as
isavuconazonium
sulphate)
% Protein binding >99
% Excreted unchanged in urine <1
Volume of distribution (L/kg) 450 Litres
Half-life - normal/ESRF (hrs) 2-4 (as isavuconazole);
80-130 (as
isavuconazonium) /
Unchanged
Check Digit Verification of cas no
The CAS Registry Mumber 241479-67-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,4,1,4,7 and 9 respectively; the second part has 2 digits, 6 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 241479-67:
(8*2)+(7*4)+(6*1)+(5*4)+(4*7)+(3*9)+(2*6)+(1*7)=144
144 % 10 = 4
So 241479-67-4 is a valid CAS Registry Number.
241479-67-4Relevant articles and documents
AN IMPROVED PROCESS FOR THE PREPARATION OF TRIAZOLE DERIVATIVES
-
, (2021/12/31)
The present invention relates to an improved process for the preparation of triazole derivatives such as ravuconazole and isavuconazole.
Crystal form of isavuconazole and preparation method thereof
-
Paragraph 0106-0117; 0120-0125, (2019/01/24)
The invention relates to a crystal form I of isavuconazole, a preparation method and application thereof. X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, hygroscopicity analysis and other means are employed for comprehensive characterization of the crystal form I of isavuconazole, and the invention finds that the crystal form I has more excellent stability than amorphism. The preparation method of the crystal form I of isavuconazole has the characteristics of simple operation, easy control and good reproducibility.
Method for manufacturing isavuconazole or ravuconazole
-
, (2017/08/27)
The invention provides a method for manufacturing a triazole compound isavuconazole or ravuconazole which is enriched by a diastereoisomer and enantiomer. The method comprises the following steps: a Reformatsky reaction is carried out between ketone and dihalogeno metal propionitrile; an enantiomer mixture is generated, and separation is carried out. The method can obviously reduce steps for synthesis of isavuconazole or ravuconazole, yield of products is improved, and production cost is reduced.
