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
- Weight
- Average: 358.4
Monoisotopic: 358.101208464 - Chemical Formula
- C16H15FN6OS
- Synonyms
- Fezolinetant
- External IDs
- ESN 364
- ESN-364
Pharmacology
- Indication
Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause.6,7
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Moderate to severe vasomotor symptoms •••••••••••• •••••• ••••••• •••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Fezolinetant has a high affinity for the NK3 receptor (Ki 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 antagonistHumans - Absorption
In healthy women, fezolinetant Cmax 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 Cmax 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 (t1/2) 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
- 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 softwareAbametapir 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
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- 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 US Veozah Tablet, film coated 45 mg/1 Oral Astellas Pharma US, Inc. 2023-05-16 Not applicable US Veozah Tablet, film coated 45 mg/1 Oral Astellas Pharma US, Inc. 2023-05-12 Not applicable US
Categories
- ATC Codes
- G02CX06 — Fezolinetant
- Drug Categories
- 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 show 7 more
- Substituents
- 1,2,4-triazole / 4-halobenzoic acid or derivatives / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzamide / Benzoyl / Carboxamide group show 19 more
- 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
- 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]
- 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]
- 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]
- 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]
- 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]
- FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]
- EMA Summary of Product Characteristics: Veoza (fezolinetant) film-coated tablets for oral administration [Link]
- Astellas Newsroom: Astellas' VEOZA™ (fezolinetant) Approved by European Commission for Treatment of Vasomotor Symptoms Associated with Menopause [Link]
- External Links
- ChemSpider
- 58828046
- BindingDB
- 50112244
- 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 US US9987274 No 2018-06-05 2034-03-28 US US9422299 No 2016-08-23 2034-03-28 US US8871761 No 2014-10-28 2031-04-04 US
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
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- 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
- 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]
- FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]
Drug created at April 20, 2020 15:29 / Updated at February 15, 2024 07:14