Identification
- Summary
Oteseconazole is an azole antifungal used to prevent recurrent vulvovaginal candidiasis in females who are not of reproductive potential.
- Brand Names
- Vivjoa
- Generic Name
- Oteseconazole
- DrugBank Accession Number
- DB13055
- Background
Oteseconazole is an azole metalloenzyme inhibitor that targets fungal CYP51.5 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.5,1 By binding and inhibiting CYP51, oteseconazole is active against most microorganisms associated with recurrent vulvovaginal candidiasis (RVVC).5 Oteseconazole has demonstrated activity against Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida lusitaniae and Candida dubliniensis.5
Unlike previous-generation azole antifungals, oteseconazole has a high selectivity for CYP51 and little interaction with human cytochrome P450s.3 This is possible thanks to the tetrazole moiety in oteseconazole that increases target selectivity.3 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.4
The use of oteseconazole is contraindicated in females of reproductive potential due to its embryo-fetal toxicity risks.5 This drug was approved by the FDA on April 26, 2022.6
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Oteseconazole (DB13055)
- Weight
- Average: 527.403
Monoisotopic: 527.119221916 - Chemical Formula
- C23H16F7N5O2
- Synonyms
- (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
- 2-Pyridineethanol, α-(2,4difluorophenyl)-β β-difluoro- α-(1H-tetrazol-1-ylmethyl)-5-(4-(2,2,2-trifluoroethoxy)phenyl)-,(αR)
- Oteseconazole
- VT-1161
- External IDs
- VT-1161
Pharmacology
- 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.5
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Recurrent vulvovaginal candidiasis •••••••••••• ••••• ••••••• •• ••••••••• •••••••••••• ••••••••••• ••••••• - Contraindications & Blackbox Warnings
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Oteseconazole is a highly selective inhibitor of fungal CYP51.5 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.3,5 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.2 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.5
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.5 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).
- 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.5 In yeast and fungi, the formation of ergosterol plays an important role in the integrity, permeability and fluidity of cell membranes.5,1 Therefore, because of its ability to bind and inhibit CYP51, oteseconazole is active against most microorganisms associated with recurrent vulvovaginal candidiasis (RVVC).5 Besides blocking the formation of ergosterol, oteseconazole also promotes the accumulation of 14-methylated sterols that lead to fungal cell death.5 To limit off-target toxicity, oteseconazole has a tetrazole metal-binding group that gives it a lower affinity for the human CYP51 isoenzyme.5
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).5 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.5 As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.
Target Actions Organism ACytochrome P450 51 inhibitorYeast - Absorption
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.5 The tmax of oteseconazole ranged from 5 to 10 hours.5 Sex, race/ethnicity, and mild to moderate renal impairment do not have a significant effect on the pharmacokinetics of oteseconazole.5
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.5 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.3 Pre-clinical studies have shown that oteseconazole exposure in vaginal tissue is similar to plasma exposure.5
- Volume of distribution
On average, the volume of distribution of oteseconazole is 423 L.5
- Protein binding
About 99.5-99.7% of oteseconazole is bound to plasma proteins.5
- Metabolism
Oteseconazole does not undergo significant metabolism.5
- Route of elimination
The majority of oteseconazole is excreted via feces and bile, and low levels of it can be found in urine.3
- Half-life
The median terminal half-life of oteseconazole is approximately 138 days.5
- Clearance
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.3
- Adverse Effects
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Based on animal studies, oteseconazole may cause embryo-fetal toxicity.5 Additional toxicity information regarding oteseconazole is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects. In case of overdose, symptomatic and supportive measures are recommended.
In a murine carcinogenicity study, Sprague Dawley rats were administered 0.5, 1.5, or 5 mg/kg/day of oral oteseconazole. Due to high mortality, the highest dose was reduced to 3 mg/kg/day.5 After 77 weeks, rats receiving 5 times the maximum recommended human dose had a higher incidence of hemorrhage in the adrenals, brain, coagulating gland, ears, epididymides, head, heart, lung, nose, pancreas, pharynx, prostate, seminal vesicles, spinal cord, testes, thymus, and bladder.5 At 26 weeks, rats receiving 5 mg/kg/day of oteseconazole did not have a higher incidence of hemorrhage. These animal studies were performed using very high doses of oteseconazole (5 to 7 times the maximum recommended human dose), and their clinical relevance remains unclear.5
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Oteseconazole. Afatinib The serum concentration of Afatinib can be increased when it is combined with Oteseconazole. Allopurinol The serum concentration of Allopurinol can be increased when it is combined with Oteseconazole. Almasilate Almasilate can cause a decrease in the absorption of Oteseconazole resulting in a reduced serum concentration and potentially a decrease in efficacy. Alpelisib The serum concentration of Alpelisib can be increased when it is combined with Oteseconazole. - Food Interactions
- Take with food. Oteseconazole must be taken with food, and capsules must be swallowed whole and not chewed, crushed, dissolved, or opened. The intake of high-fat, high-calorie meals (800-1000 Calories; 50% fat) increases oteseconazole Cmax and AUC0-72h by 45% and 36%, respectively. No significant differences were detected when oteseconazole was administered with a low-fat, low-calorie meal.
Products
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- Vivjoa (Mycovia Pharmaceuticals, Inc.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Vivjoa Capsule 150 mg/1 Oral Mycovia Pharmaceuticals, Inc. 2022-07-11 Not applicable US 
Categories
- ATC Codes
- J02AC06 — Oteseconazole
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylpyridines. These are polycyclic aromatic compounds containing a benzene ring linked to a pyridine ring through a CC or CN bond.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Pyridines and derivatives
- Sub Class
- Phenylpyridines
- Direct Parent
- Phenylpyridines
- Alternative Parents
- Phenoxy compounds / Phenol ethers / Fluorobenzenes / Alkyl aryl ethers / Aryl fluorides / Tetrazoles / Tertiary alcohols / Heteroaromatic compounds / Fluorohydrins / Azacyclic compounds show 5 more
- Substituents
- 3-phenylpyridine / Alcohol / Alkyl aryl ether / Alkyl fluoride / Alkyl halide / Aromatic alcohol / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle show 20 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Candida albicans and other yeasts
Chemical Identifiers
- UNII
- VHH774W97N
- CAS number
- 1340593-59-0
- InChI Key
- IDUYJRXRDSPPRC-NRFANRHFSA-N
- InChI
- 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
- IUPAC Name
- (2R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,3,4-tetrazol-1-yl)-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol
- SMILES
- O[C@@](CN1C=NN=N1)(C1=CC=C(F)C=C1F)C(F)(F)C1=CC=C(C=N1)C1=CC=C(OCC(F)(F)F)C=C1
References
- Synthesis Reference
Hoekstra, WJ., et al. (2020). Antifungal compound process (U.S. Patent No. US 10,745,378 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/f4/62/19/5ba525b1caad0e/US10745378.pdf
- General References
- Zhang J, Li L, Lv Q, Yan L, Wang Y, Jiang Y: The Fungal CYP51s: Their Functions, Structures, Related Drug Resistance, and Inhibitors. Front Microbiol. 2019 Apr 24;10:691. doi: 10.3389/fmicb.2019.00691. eCollection 2019. [Article]
- Brand SR, Sobel JD, Nyirjesy P, Ghannoum MA, Schotzinger RJ, Degenhardt TP: A Randomized Phase 2 Study of VT-1161 for the Treatment of Acute Vulvovaginal Candidiasis. Clin Infect Dis. 2021 Oct 5;73(7):e1518-e1524. doi: 10.1093/cid/ciaa1204. [Article]
- Sobel JD, Nyirjesy P: Oteseconazole: an advance in treatment of recurrent vulvovaginal candidiasis. Future Microbiol. 2021 Dec;16:1453-1461. doi: 10.2217/fmb-2021-0173. Epub 2021 Nov 16. [Article]
- Chang YL, Yu SJ, Heitman J, Wellington M, Chen YL: New facets of antifungal therapy. Virulence. 2017 Feb 17;8(2):222-236. doi: 10.1080/21505594.2016.1257457. Epub 2016 Nov 7. [Article]
- FDA Approved Drug Products: Vivjoa (oteseconazole) oral capsules [Link]
- FDA Letter of Approval: Vivjoa (oteseconazole) oral capsules [Link]
- External Links
- PubChem Compound
- 77050711
- PubChem Substance
- 347829184
- ChemSpider
- 52083215
- BindingDB
- 50046187
- 2602577
- ChEBI
- 188153
- ChEMBL
- CHEMBL3311228
- ZINC
- ZINC000167574450
- PDBe Ligand
- VT1
- Wikipedia
- Oteseconazole
- PDB Entries
- 5ajr / 5tz1 / 5ul0 / 8ekt
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 3 Completed Treatment Recurrent Vulvovaginal Candidiasis 3 2 Completed Treatment Onychomycosis 1 2 Completed Treatment Recurrent Vulvovaginal Candidiasis 1 2 Completed Treatment Tinea Pedis 1 2 Completed Treatment Vulvovaginal Candidiasis 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 150 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11247981 No 2013-05-09 2033-05-09 US US8754227 No 2014-06-17 2031-04-22 US US8236962 No 2012-08-07 2031-04-22 US US9840492 No 2017-12-12 2036-03-17 US US10414751 No 2019-09-17 2036-03-17 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Insoluble at a pH range of 1 to 9 FDA label - Predicted Properties
Property Value Source Water Solubility 0.00458 mg/mL ALOGPS logP 3.93 ALOGPS logP 4.69 Chemaxon logS -5.1 ALOGPS pKa (Strongest Acidic) 10.67 Chemaxon pKa (Strongest Basic) 2.01 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 85.95 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 128.23 m3·mol-1 Chemaxon Polarizability 44.38 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 206.13762 predictedDeepCCS 1.0 (2019) [M+H]+ 208.53319 predictedDeepCCS 1.0 (2019) [M+Na]+ 214.44574 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Yeast
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Sterol 14-demethylase activity
- Specific Function
- Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
- Gene Name
- ERG11
- Uniprot ID
- P10613
- Uniprot Name
- Lanosterol 14-alpha demethylase
- Molecular Weight
- 60674.965 Da
References
- FDA Approved Drug Products: Vivjoa (oteseconazole) oral capsules [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
References
- FDA Approved Drug Products: Vivjoa (oteseconazole) oral capsules [Link]
Drug created at October 21, 2016 02:29 / Updated at May 03, 2022 17:30