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General Description:

Ibrexafungerp, identified by CAS number 1207753-03-4, is a notable compound with significant therapeutic applications. Ibrexafungerp, also known as SCY-078 or MK-3118, is a novel enfumafungin derivative oral triterpene antifungal approved for the treatment of vulvovaginal candidiasis (VVC), also known as a vaginal yeast infection. It was developed out of a need to treat fungal infections that may have become resistant to echinocandins or azole antifungals. Ibrexafungerp is orally bioavailable compared to the echinocandins , , and ; which can only be administered parenterally. Similar to echinocandins, ibrexafungerp targets the fungal β-1,3-glucan synthase, which is not present in humans, limiting the chance of renal or hepatic toxicity. Ibrexafungerp was granted FDA approval on 1 June 2021.

Indications:

This drug is primarily indicated for: Ibrexafungerp is indicated in the treatment of vulvovaginal candidiasis in post-menarchal patients. It is also indicated for the reduction in the incidence of recurrent vulvovaginal candidiasis. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Ibrexafungerp undergoes metabolic processing primarily in: Ibrexafungerp is hydroxylated by CYP3A4 before glucuronide or sulfate conjugation of the hydroxyl group before elimination. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Ibrexafungerp are crucial for its therapeutic efficacy: Ibrexafungerp given at a dose of 300 mg twice daily reaches a C_max of 435 ng/mL, with a T_max of 4-6 hours, and an AUC_0-24 of 6832 h\*ng/mL. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Ibrexafungerp is an important consideration for its dosing schedule: The elimination half life of ibrexafungerp is approximately 20 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Ibrexafungerp exhibits a strong affinity for binding with plasma proteins: Ibrexafungerp is 99.5-99.8% protein bound in plasma, mainly to albumin. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Ibrexafungerp from the body primarily occurs through: 90% of a radiolabelled oral dose of ibrexafungerp is recovered in the feces, with 51% as the unchanged parent drug. 1% of a radiolabelled oral dose is recovered in the urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Ibrexafungerp is distributed throughout the body with a volume of distribution of: The volume of distribution at steady state is approximately 600 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Ibrexafungerp is a critical factor in determining its safe and effective dosage: Clearance values of 53.6 L/h and 56.1 L/h have been reported. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Ibrexafungerp exerts its therapeutic effects through: Ibrexafungerp is an enfumafungin derivative oral triterpene antifungal approved for the treatment of vulvovaginal candidiasis. It has a moderate duration of action, as it is taken twice daily, and a wide therapeutic index as patients took more than the recommended dose in clinical trials without severe adverse effects. Patients should be counselled regarding the risk of fetal toxicity. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Ibrexafungerp functions by: β-1,3-glucan synthase is composed of a catalytic subunit, FKS1 or FKS2, and a GTP-binding regulatory subunit, Rho1. This synthase is involved in the synthesis of β-1,3-glucan, a fungal cell wall component. Ibrexafungerp acts similarly to the echinocandin antifungals, by inhibiting the synthesis of β-1,3-glucan synthase. While echinocandins bind to the FKS1 domain of β-1,3-glucan synthase, enfumafungin and its derivatives bind at an alternate site which allows them to maintain their activity against fungal infections that are resistant to echinocandins. Ibrexafungerp has been shown in animal studies to distribute well to vaginal tissue, making it a favourable treatment for vulvovaginal candidiasis. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Ibrexafungerp belongs to the class of organic compounds known as hydroxysteroids. These are compounds containing an steroid backbone, with at least one hydrogen substituted by a hydroxyl group, classified under the direct parent group Hydroxysteroids. This compound is a part of the Organic compounds, falling under the Lipids and lipid-like molecules superclass, and categorized within the Steroids and steroid derivatives class, specifically within the Hydroxysteroids subclass.

Categories:

Ibrexafungerp is categorized under the following therapeutic classes: Anti-Infective Agents, Antifungal Agents, Carbohydrates, Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (strength unknown), Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (strength unknown), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, OATP1B3 inhibitors, P-glycoprotein substrates, Terpenes, Triterpenes, Triterpenoid Antifungal, Triterpenoid Antifungals. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Ibrexafungerp include:

• pKa: 2.4, 5.5, 9.0