Fezolinetant

Identification

Summary

Fezolinetant is a non-hormonal drug used to treat moderate to severe vasomotor symptoms due to menopause.

Brand Names

Veozah

Generic Name

Fezolinetant

DrugBank Accession Number

DB15669

Background

Vasomotor symptoms (VMS), more colloquially known as hot flashes or night sweats, are some of the most common symptoms in menopause. With a median duration of 7.4 years, vasomotor symptoms are also the most common reasons why women seek treatments for menopausal issues.^1,2 Although mostly considered a nuisance, vasomotor symptoms can significantly affect quality of life, as women with 7 or more moderate to severe VMS daily have reported a decline in sleep quality, concentration, sexual activity, energy, and concentration.³

Although the pathophysiology of VMS is not fully understood, unpredictable fluctuation in estrogen levels is thought to be the main cause of VMS, as estrogen therapy has been one of the most effective treatments for VMS by relieving symptoms in as many as 95% of menopausal women. Women undergoing abrupt menopause due to oophorectomy also experienced more severe symptoms than those going through a gradual transition.^4,3 Additionally, thermoregulatory dysfunction has been proposed as one of the three possible mechanisms for VMS in menopause.⁴ Estrogen is a potent neuromodulator, particularly in the hypothalamus, and has been shown to be involved as a negative regulator in generating Gonadotropin-releasing hormone (GnRH) pulse through the kisspeptin, neurokinin B, and dynorphin (KNDy) neurons.^1,5 NK3, one of the receptors expressed in KNDy neurons, is activated by neurokinin B and can thus induce the release of GnRH.^1,5 Lower estrogen levels during menopause will decrease the estrogen-mediated feedback loop and increase neurokinin B signalling, increasing the activity of KNDy neurons and therefore the activity of the temperature control center.^1,5 By antagonizing NK3 receptors, neuronal signalling can be dampened to reduce VMS.^1,5

Although hormone therapy is available for menopausal women, safety and tolerability concerns, such as an increased risk of stroke and venous thromboembolism or hormone-dependent cancer like breast cancer, can prevent some women from receiving this treatment.⁵ Fezolinetant, an NK3 receptor antagonist, was developed in response to this issue as well as more understanding of the role of NK3R in the hypothalamic-pituitary-gonadal (HPG) axis.⁵ Although previous NK3 receptor antagonists exist, such as osanetant and talnetant, only fezolinetant showed tangible effects on the HPC axis, potentially due to its favorable pharmacokinetics profile to cross the blood-brain barrier.⁵

Fezolinetant was approved by the FDA in May 2023 under the brand name Veozah.⁶ It was subsequently approved by the EMA in December 2023 for the same indication.⁸

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Fezolinetant (DB15669)

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Weight

Average: 358.4
Monoisotopic: 358.101208464

Chemical Formula

C₁₆H₁₅FN₆OS

Synonyms

• Fezolinetant

External IDs

• ESN 364
• ESN-364

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Pharmacology

Indication

Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause.^6,7

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Moderate to severe vasomotor symptoms		••••••••••••	•••••• •••••••		••••••

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Pharmacodynamics

Fezolinetant has a high affinity for the NK3 receptor (K_i value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than the binding affinity for NK1 or NK2 receptors.⁶

Treatment with fezolinetant did not show any clear trends in sex hormones measured (follicle-stimulating hormone, testosterone, estrogen, and dehydroepiandrosterone sulfate) in menopausal women. A transient decrease of luteinizing hormone (LH) levels was observed at peak concentrations of fezolinetant. At a dose 20 times the maximum approved recommended dose, fezolinetant does not prolong the QT interval to any clinically relevant extent.⁶

In a phase 2a clinical trial, fezolinetant 90 mg BID significantly reduce the frequency and severity of vasomotor symptoms in postmenopausal women by more than 50%. The improvement was observed as early as in the first week of treatment and was maintained throughout the 12 weeks of treatment.¹

Mechanism of action

Fezolinetant is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center.⁶

Target	Actions	Organism
ANeuromedin-K receptor	antagonist	Humans

Absorption

In healthy women, fezolinetant C_max and AUC increased proportionally over a dosage range from 20 to 60 mg once daily (0.44 to 1.33 times the approved recommended dosage). Steady-state plasma concentrations of fezolinetant were reached after two once-daily doses, with minimal fezolinetant accumulation. The median (range) time to reach fezolinetant C_max is 1.5 (1 to 4) hours in healthy women.⁶

Volume of distribution

The mean apparent volume of distribution (Vz/F) of fezolinetant is 189 L.⁶

Protein binding

The plasma protein binding of fezolinetant is 51%. The blood-to-plasma ratio is 0.9.⁶

Metabolism

Fezolinetant is primarily metabolized by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19. A major metabolite of fezolinetant, ES259564, was identified in plasma. ES259564 is approximately 20-fold less potent than the parent. The metabolite-to-parent ratio ranges from 0.7 to 1.8.⁶

Route of elimination

Following oral administration of fezolinetant, 76.9% of the dose was excreted in urine (1.1% unchanged) and 14.7% in feces (0.1% unchanged).⁶

Half-life

The effective half-life (t_1/2) of fezolinetant is 9.6 hours in women with vasomotor symptoms.⁶

Clearance

The apparent clearance at steady state of fezolinetant is 10.8 L/h.⁶

Adverse Effects

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Toxicity

In embryo-fetal development toxicity studies in rats and rabbits, embryo-lethality was noted at the highest doses (128- and 174-fold the human AUC₂₄ at the human therapeutic dose for rats and rabbits, respectively). The no observed adverse effect level (NOAEL) for embryo-fetal development was 50 mg/kg/day in rats and 45 mg/kg/day in rabbits (62- and 16-fold the human AUC₂₄ at the human therapeutic dose for rats and rabbits, respectively). Fezolinetant showed no effects on fertility and early embryonic development in rats.⁶

In the pre-and post-natal development study in rats, the NOAEL for maternal and fetal toxicity was 30 mg/kg/day (36-fold the human AUC₂₄ at the human therapeutic dose) based on delayed parturition and embryo-lethality at 100 mg/kg/day. The NOAEL for F1 generation development was determined to be 100 mg/kg/day for females (204-fold the human AUC₂₄ at the human therapeutic dose) and 10 mg/kg/day for males (11-fold the human AUC₂₄ at the human therapeutic dose).⁶

In the pre-and post-natal development study in rats, the F1 male showed incomplete balanopreputial separation at doses greater than or equal to 30 mg/kg/day (36-fold the human AUC₂₄ at the human therapeutic dose), which delayed male reproductive maturation and affected fertility. These effects were not observed following dosing at 10 mg/kg/day (11-fold the human AUC₂₄ at the human therapeutic dose).⁶

Repeat dose toxicity studies were conducted in intact female rats and cynomolgus monkeys. In female rats, daily administration of fezolinetant for 26 weeks at doses equal to or greater than 30 mg/kg/day (56-fold the human AUC₂₄ at the human therapeutic dose) showed uterine atrophy and epithelial mucification of the vagina and cervix. In female cynomolgus monkeys, daily administration for 39 weeks at doses equal to or greater than 10 mg/kg/day (19-fold the human AUC₂₄ at the human therapeutic dose) showed reduced ovarian activity.⁶

Fezolinetant is contraindicated in individuals with severe (eGFR 15 to less than 30 mL/min/1.73 m²) renal impairment or end-stage renal disease (eGFR less than 15 mL/min/1.73 m²). No dose adjustment of fezolinetant is recommended for individuals with mild (eGFR 60 to less than 90 mL/min/1.73 m²) or moderate (eGFR 30 to less than 60 mL/min/1.73 m²) renal impairment.⁶

Child-Pugh Class A or B hepatic impairment increased the exposure to fezolinetant. Fezolinetant has not been studied in individuals with Child-Pugh Class C hepatic impairment.⁶

In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC₂₄ at the human therapeutic dose of 45 mg, respectively.⁶

Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test.⁶

Treatment of overdose consists of discontinuation of fezolinetant therapy with the institution of appropriate symptomatic care.⁶

Pathways

Not Available

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Interactions

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Fezolinetant can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Fezolinetant can be increased when combined with Abatacept.
Abiraterone	The serum concentration of Fezolinetant can be increased when it is combined with Abiraterone.
Acenocoumarol	The metabolism of Fezolinetant can be decreased when combined with Acenocoumarol.
Acetaminophen	The metabolism of Fezolinetant can be decreased when combined with Acetaminophen.

Food Interactions

Not Available

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Veozah	Tablet, film coated	45 mg/1	Oral	Astellas Pharma US, Inc.	2023-05-12	Not applicable
Veozah	Tablet, film coated	45 mg/1	Oral	Astellas Pharma US, Inc.	2023-05-16	Not applicable
Veozah	Tablet, film coated	45 mg/1	Oral	Astellas Pharma US, Inc.	2023-05-12	Not applicable

Categories

ATC Codes

G02CX06 — Fezolinetant

• G02CX — Other gynecologicals
• G02C — OTHER GYNECOLOGICALS
• G02 — OTHER GYNECOLOGICALS
• G — GENITO URINARY SYSTEM AND SEX HORMONES

Drug Categories

• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 Substrates
• Genito Urinary System and Sex Hormones
• Heterocyclic Compounds, Fused-Ring
• Sulfur Compounds
• Thiazoles

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as 4-halobenzoic acids and derivatives. These are benzoic acids or derivatives carrying a halogen atom at the 4-position of the benzene ring.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Benzoic acids and derivatives

Direct Parent

4-halobenzoic acids and derivatives

Alternative Parents

Triazolopyrazines / Benzamides / Benzoyl derivatives / Fluorobenzenes / Aryl fluorides / Pyrazines / Heteroaromatic compounds / Tertiary carboxylic acid amides / Thiadiazoles / Triazoles / Azacyclic compounds / Organooxygen compounds / Organonitrogen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives / Organopnictogen compounds

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Substituents

1,2,4-triazole / 4-halobenzoic acid or derivatives / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzamide / Benzoyl / Carboxamide group / Carboxylic acid derivative / Fluorobenzene / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Pyrazine / Tertiary carboxylic acid amide / Thiadiazole / Triazole / Triazolopyrazine

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

83VNE45KXX

CAS number

1629229-37-3

InChI Key

PPSNFPASKFYPMN-SECBINFHSA-N

InChI

InChI=1S/C16H15FN6OS/c1-9-13-19-20-14(15-18-10(2)21-25-15)23(13)8-7-22(9)16(24)11-3-5-12(17)6-4-11/h3-6,9H,7-8H2,1-2H3/t9-/m1/s1

IUPAC Name

5-[(8R)-7-(4-fluorobenzoyl)-8-methyl-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-3-methyl-1,2,4-thiadiazole

SMILES

C[C@H]1N(CCN2C1=NN=C2C1=NC(C)=NS1)C(=O)C1=CC=C(F)C=C1

References

General References

1. Santoro N, Waldbaum A, Lederman S, Kroll R, Fraser GL, Lademacher C, Skillern L, Young J, Ramael S: Effect of the neurokinin 3 receptor antagonist fezolinetant on patient-reported outcomes in postmenopausal women with vasomotor symptoms: results of a randomized, placebo-controlled, double-blind, dose-ranging study (VESTA). Menopause. 2020 Dec;27(12):1350-1356. doi: 10.1097/GME.0000000000001621. [Article]
2. Thurston RC, Joffe H: Vasomotor symptoms and menopause: findings from the Study of Women's Health across the Nation. Obstet Gynecol Clin North Am. 2011 Sep;38(3):489-501. doi: 10.1016/j.ogc.2011.05.006. [Article]
3. Pinkerton JV, Redick DL, Homewood LN, Kaunitz AM: Neurokinin receptor antagonist, fezolinetant, for treatment of menopausal vasomotor symptoms. J Clin Endocrinol Metab. 2023 Apr 25:dgad209. doi: 10.1210/clinem/dgad209. [Article]
4. Deecher DC, Dorries K: Understanding the pathophysiology of vasomotor symptoms (hot flushes and night sweats) that occur in perimenopause, menopause, and postmenopause life stages. Arch Womens Ment Health. 2007;10(6):247-57. doi: 10.1007/s00737-007-0209-5. Epub 2007 Dec 12. [Article]
5. Depypere H, Lademacher C, Siddiqui E, Fraser GL: Fezolinetant in the treatment of vasomotor symptoms associated with menopause. Expert Opin Investig Drugs. 2021 Jul;30(7):681-694. doi: 10.1080/13543784.2021.1893305. Epub 2021 Jul 12. [Article]
6. FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]
7. EMA Summary of Product Characteristics: Veoza (fezolinetant) film-coated tablets for oral administration [Link]
8. Astellas Newsroom: Astellas' VEOZA™ (fezolinetant) Approved by European Commission for Treatment of Vasomotor Symptoms Associated with Menopause [Link]

External Links

ChemSpider

58828046

BindingDB

50112244

RxNav

2637134

ChEMBL

CHEMBL3608680

ZINC

ZINC000218861630

Wikipedia

Fezolinetant

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	Coronavirus Disease 2019 (COVID‑19) / Hot Flashes	3
3	Completed	Treatment	Hot Flashes	2
3	Completed	Treatment	Vasomotor Symptoms Associated With Menopause	1
3	Not Yet Recruiting	Treatment	Hot Flashes	2
2	Completed	Treatment	Hot Flashes	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	45 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US10836768	No	2020-11-17	2034-03-28
US9987274	No	2018-06-05	2034-03-28
US9422299	No	2016-08-23	2034-03-28
US8871761	No	2014-10-28	2031-04-04

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	0.29 mg/mL	L46422

Predicted Properties

Property	Value	Source
Water Solubility	0.306 mg/mL	ALOGPS
logP	1.57	ALOGPS
logP	1.78	Chemaxon
logS	-3.1	ALOGPS
pKa (Strongest Basic)	0.87	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	76.8 Å2	Chemaxon
Rotatable Bond Count	2	Chemaxon
Refractivity	114.39 m3·mol-1	Chemaxon
Polarizability	36.15 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0009000000-5ddc1afa68de18b79a1f
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0039000000-e088bef970ae9d8bbd36
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0029000000-19755870463f43ed8157
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a73-0449000000-8d98c8ac9963500a383d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0596-0903000000-8ddbf0e86d1d310966a1
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0596-5944000000-9bf98d6bdd5a2e369bef
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Neuromedin-K receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Tachykinin receptor activity

Specific Function

This is a receptor for the tachykinin neuropeptide neuromedin-K (neurokinin B). It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order...

Gene Name

TACR3

Uniprot ID

P29371

Uniprot Name

Neuromedin-K receptor

Molecular Weight

52201.35 Da

References

1. Depypere H, Lademacher C, Siddiqui E, Fraser GL: Fezolinetant in the treatment of vasomotor symptoms associated with menopause. Expert Opin Investig Drugs. 2021 Jul;30(7):681-694. doi: 10.1080/13543784.2021.1893305. Epub 2021 Jul 12. [Article]
2. FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]

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Drug created at April 20, 2020 15:29 / Updated at February 15, 2024 07:14