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
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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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

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.

TargetActionsOrganism
ACytochrome P450 51
inhibitor
Yeast
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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Toxicity

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
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Oteseconazole.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Oteseconazole.
AllopurinolThe serum concentration of Allopurinol can be increased when it is combined with Oteseconazole.
AlmasilateAlmasilate can cause a decrease in the absorption of Oteseconazole resulting in a reduced serum concentration and potentially a decrease in efficacy.
AlpelisibThe serum concentration of Alpelisib can be increased when it is combined with Oteseconazole.
Aluminium phosphateAluminium phosphate can cause a decrease in the absorption of Oteseconazole resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminum hydroxideAluminum hydroxide can cause a decrease in the absorption of Oteseconazole resulting in a reduced serum concentration and potentially a decrease in efficacy.
AmiodaroneThe therapeutic efficacy of Oteseconazole can be increased when used in combination with Amiodarone.
AmlodipineThe therapeutic efficacy of Oteseconazole can be increased when used in combination with Amlodipine.
Amphotericin BThe therapeutic efficacy of Amphotericin B can be decreased when used in combination with Oteseconazole.
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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.

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International/Other Brands
Vivjoa (Mycovia Pharmaceuticals, Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VivjoaCapsule150 mg/1OralMycovia Pharmaceuticals, Inc.2022-07-11Not applicableUS flag

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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. FDA Approved Drug Products: Vivjoa (oteseconazole) oral capsules [Link]
  6. FDA Letter of Approval: Vivjoa (oteseconazole) oral capsules [Link]
PubChem Compound
77050711
PubChem Substance
347829184
ChemSpider
52083215
BindingDB
50046187
RxNav
2602577
ChEBI
188153
ChEMBL
CHEMBL3311228
ZINC
ZINC000167574450
PDBe Ligand
VT1
Wikipedia
Oteseconazole
PDB Entries
5ajr / 5tz1 / 5ul0

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentRecurrent Vulvovaginal Candidiasis3
2CompletedTreatmentOnychomycosis1
2CompletedTreatmentRecurrent Vulvovaginal Candidiasis1
2CompletedTreatmentTinea Pedis1
2CompletedTreatmentVulvovaginal Candidiasis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral150 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11247981No2013-05-092033-05-09US flag
US8754227No2014-06-172031-04-22US flag
US8236962No2012-08-072031-04-22US flag
US9840492No2017-12-122036-03-17US flag
US10414751No2019-09-172036-03-17US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsoluble at a pH range of 1 to 9FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.00458 mg/mLALOGPS
logP3.93ALOGPS
logP4.69Chemaxon
logS-5.1ALOGPS
pKa (Strongest Acidic)10.67Chemaxon
pKa (Strongest Basic)2.01Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area85.95 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity128.23 m3·mol-1Chemaxon
Polarizability44.38 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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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
  1. 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
  1. FDA Approved Drug Products: Vivjoa (oteseconazole) oral capsules [Link]

Drug created at October 21, 2016 02:29 / Updated at May 03, 2022 17:30