Absorption, Distribution and Excretion
Between 20 mg and 320 mg, the AUC of oteseconazole increased relatively dose proportionally, and the Cmax increased less than dose proportionally. On average, the AUC was 64.2 h·µg/mL, and the Cmax was 2.8 µg/mL at the end of recurrent vulvovaginal candidiasis (RVVC) treatment. The tmax of oteseconazole ranged from 5 to 10 hours. Sex, race/ethnicity, and mild to moderate renal impairment do not have a significant effect on the pharmacokinetics of oteseconazole. The bioavailability of oteseconazole is affected by high-fat, high-calorie meals. With a diet that had 800-1000 Calories and 50% fat, Cmax and AUC0-72h were 45% and 36% higher, respectively. No significant differences were detected with a low-fat, low-calorie meal. Animal models have shown that the bioavailability of oteseconazole is high. In a murine model, bioavailability was 73%. In dogs, bioavailability was 40% after fasting, and 100% in a fed state. Pre-clinical studies have shown that oteseconazole exposure in vaginal tissue is similar to plasma exposure.
The majority of oteseconazole is excreted via feces and bile, and low levels of it can be found in urine.
On average, the volume of distribution of oteseconazole is 423 L.
Clinical phase I studies performed in healthy adults found that the clearance of oteseconazole is not affected by age or sex, and that the relationship between weight and clearance is approximately linear. The clearance of oteseconazole in non-white participants was 48% higher than the one detected in white participants, although the reasons for this are unknown.

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Metabolism / Metabolites
Oteseconazole does not undergo significant metabolism.

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Biological Half-Life
The median terminal half-life of oteseconazole is approximately 138 days.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Oteseconazole must not be used by women of reproductive potential because of the possibility of fetal harm. It is extremely long-lasting and could remain in the milk for as long as 2 years after a course of therapy. An alternate drug should be used.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
About 99.5-99.7% of oteseconazole is bound to plasma proteins.

[1].Warrilow AG, et al. The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme. Antimicrob Agents Chemother. 2014 Dec;58(12):7121-7.

[2].Garvey EP, et al. VT-1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a guinea pig model. Antimicrob Agents Chemother. 2015 Apr;59(4):1992-7.

[3].https://www.pharmacytimes.com/view/fda-approves-osteseconazole-for-recurrent-vulvovaginal-candidiasis

Oteseconazole is an organic molecular entity.
Oteseconazole is an azole metalloenzyme inhibitor that targets fungal CYP51. CYP51, also known as 14α demethylase, participates in the formation of ergosterol, a compound that plays a vital role in the integrity of cell membranes. By binding and inhibiting CYP51, oteseconazole is active against most microorganisms associated with recurrent vulvovaginal candidiasis (RVVC). Oteseconazole has demonstrated activity against Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida lusitaniae and Candida dubliniensis. Unlike previous-generation azole antifungals, oteseconazole has a high selectivity for CYP51 and little interaction with human cytochrome P450s. This is possible thanks to the tetrazole moiety in oteseconazole that increases target selectivity. In contrast with oteseconazole, other antifungals with imidazole or triazole moieties, such as [ketoconazole] or [fluconazole], have a high number of drug-drug interactions due to their interaction with human CYPs. The use of oteseconazole is contraindicated in females of reproductive potential due to its embryo-fetal toxicity risks. This drug was approved by the FDA on April 26, 2022.
Oteseconazole is an Azole Antifungal. The mechanism of action of oteseconazole is as a Breast Cancer Resistance Protein Inhibitor.

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Drug Indication
Oteseconazole is an azole antifungal indicated to reduce the incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC who are not of reproductive potential.
Treatment of vulvovaginal candidiasis

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Mechanism of Action
Oteseconazole is an azole metalloenzyme inhibitor that targets CYP51 (also known as 14α demethylase), an enzyme that demethylates the 14-α position of lanosterol to form ergosterol. In yeast and fungi, the formation of ergosterol plays an important role in the integrity, permeability and fluidity of cell membranes. Therefore, because of its ability to bind and inhibit CYP51, oteseconazole is active against most microorganisms associated with recurrent vulvovaginal candidiasis (RVVC). Besides blocking the formation of ergosterol, oteseconazole also promotes the accumulation of 14-methylated sterols that lead to fungal cell death. To limit off-target toxicity, oteseconazole has a tetrazole metal-binding group that gives it a lower affinity for the human CYP51 isoenzyme. Mechanisms of drug resistance were evaluated _in vitro_, and increases in oteseconazole minimum inhibitory concentrations were associated with the upregulation of efflux pumps CDR1 and MDR1, and the azole target itself (CYP51). Oteseconazole had _in vitro_ activity against _Candida_ spp. that were resistant to fluconazole, and it was active against most of the microorganisms associated with RVVC: _Candida albicans_, _Candida glabrata_, _Candida krusei_, _Candida parapsilosis_, _Candida tropicalis_, _Candida lusitaniae_ and _Candida dubliniensis_. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.

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Pharmacodynamics
Oteseconazole is a highly selective inhibitor of fungal CYP51. By targeting CYP51, oteseconazole inhibits the formation of ergosterol, a sterol required to form and maintain the integrity of fungal cell membranes. The tetrazole metal-binding group of oteseconazole increases its selectivity for fungal CYP51 and reduces off-target interactions with human cytochrome P450s. A phase 2 clinical trial that included women with vulvovaginal candidiasis reported that oteseconazole was safe and well-tolerated up to 600 mg twice daily. The exposure-response relationships and the time course of pharmacodynamic response of oteseconazole are not known. At 5-times the maximum exposures for the recommended dose, oteseconazole does not have a clinically relevant effect on QT-prolongation. Oteseconazole is contraindicated in pregnant and lactating women and females of reproductive potential since it may cause fetal harm. The exposure window of oteseconazole is 690 days, and it precludes any mitigation measures to avoid the risk of toxicity. Several ocular abnormalities were detected in animal studies. Some of the abnormalities detected in the offspring of pregnant rats that received 7.5 mg/kg/day of oteseconazole from organogenesis to lactation were: cataracts, opacities, exophthalmos/buphthalmos, optic nerve/retinal atrophy, lens degeneration and hemorrhage. The doses used in animal studies correspond to 3.5 times the clinical exposure detected in patients treated for recurrent vulvovaginal candidiasis (RVVC).

C23H16F7N5O2

527.4

527.119

1340593-59-0

77050711

White to off-white solid powder

1.5±0.1 g/cm3

609.2±65.0 °C at 760 mmHg

322.3±34.3 °C

0.0±1.8 mmHg at 25°C

1.570

5.7

1

13

8

37

743

1

C1=CC(=CC=C1C2=CN=C(C=C2)C([C@](CN3C=NN=N3)(C4=C(C=C(C=C4)F)F)O)(F)F)OCC(F)(F)F

IDUYJRXRDSPPRC-NRFANRHFSA-N

InChI=1S/C23H16F7N5O2/c24-16-4-7-18(19(25)9-16)21(36,11-35-13-32-33-34-35)23(29,30)20-8-3-15(10-31-20)14-1-5-17(6-2-14)37-12-22(26,27)28/h1-10,13,36H,11-12H2/t21-/m0/s1

(R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol

VT 1161 VivjoaVT-1161 Oteseconazole.

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 : ~250 mg/mL (~474.03 mM)

Solubility in Formulation 1: ≥ 2.25 mg/mL (4.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 22.5 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: ≥ 2.25 mg/mL (4.27 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 22.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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