Indications
Oteseconazole is an azole antifungal specifically approved for the reduction of recurrent vulvovaginal candidiasis (RVVC) in females who are not of reproductive potential and have a history of RVVC. It is important to note that oteseconazole is contraindicated in pregnant and lactating women, as well as females of reproductive potential, due to potential fetal harm.
Pharmacodynamics
Oteseconazole functions as a highly selective inhibitor of fungal CYP51. By inhibiting this enzyme, oteseconazole prevents the formation of ergosterol, which is vital for maintaining the integrity of fungal cell membranes. The drug's tetrazole metal-binding group contributes to its selectivity for fungal CYP51 and limits off-target interactions with human cytochrome P450s. Clinical evaluations have demonstrated that oteseconazole is generally safe and well-tolerated at doses up to 600 mg twice daily. Notably, oteseconazole does not exhibit clinically meaningful effects on QT-prolongation at exposure levels up to five times the maximum recommended dose. However, it is associated with potential ocular abnormalities as observed in animal studies when administered during specific developmental periods.
Absorption
The pharmacokinetics of oteseconazole reveal that the area under the curve (AUC) increases relatively dose-proportionally between 20 mg and 320 mg, while the peak concentration (Cmax) increases less than dose proportionally. At the conclusion of RVVC treatment, the average AUC and Cmax were recorded as 64.2 h·µg/mL and 2.8 µg/mL, respectively. The time to reach maximum concentration (tmax) ranges from 5 to 10 hours. Oteseconazole's pharmacokinetics are not significantly influenced by sex, race/ethnicity, or mild to moderate renal impairment. High-fat and high-calorie meals can increase Cmax and AUC0-72h, demonstrating the influence of dietary intake on bioavailability.
Metabolism
Oteseconazole does not undergo significant metabolic alteration in the body, maintaining its pharmacological activity largely unchanged. This metabolic stability contributes to its sustained therapeutic effects during the treatment of RVVC.
Mechanism of Action
Oteseconazole functions as an azole metalloenzyme inhibitor, specifically targeting the enzyme CYP51, also known as 14α-demethylase. This enzyme is crucial for the demethylation at the 14-α position of lanosterol, resulting in the production of ergosterol. Ergosterol is essential for maintaining the integrity, permeability, and fluidity of fungal cell membranes. By binding to and inhibiting CYP51, oteseconazole is effective against many microorganisms responsible for recurrent vulvovaginal candidiasis (RVVC). In addition to preventing ergosterol synthesis, oteseconazole induces the accumulation of 14-methylated sterols, which contribute to fungal cell death. The drug is designed with a tetrazole metal-binding group to minimize off-target effects by reducing its affinity for the human CYP51 isoenzyme.
