Identification
- Name
- Vibegron
- Accession Number
- DB14895
- Description
Vibegron is a potent, selective beta-3 adrenergic receptor (β3) agonist that relaxes the detrusor smooth muscle of the bladder, thereby increasing bladder capacity.6 Vibegron was first approved in Japan in September 2018 for the treatment of overactive bladder,1 a condition associated with distressing symptoms of urge urinary incontinence, urgency, and urinary frequency, and reduced quality of life of patients. On December 23, 2020, vibegron was approved for the same indication in adults. It is available as oral tablets under the market name GEMTESA.7
Vibegron is the second beta-3 adrenergic agonist approved for the treatment of overactive bladder following mirabegron, which was approved in 2012. Unlike mirabegron, vibegron is less likely to be associated with drug-drug interactions involving the CYP3A4, 2D6, or 2C9 enzymes.4
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 444.535
Monoisotopic: 444.216140778 - Chemical Formula
- C26H28N4O3
- Synonyms
- Vibegron
- Vibégron
- Vibegrón
- Vibegronum
- External IDs
- KRP-114V
- MK 4618
Pharmacology
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- Indication
Vibegron is indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults.6
- Associated Conditions
- Contraindications & Blackbox Warnings
- Contraindications & Blackbox WarningsWith our commercial data, access important information on dangerous risks, contraindications, and adverse effects.Our Blackbox Warnings cover Risks, Contraindications, and Adverse Effects
- Pharmacodynamics
Vibegron selectivity for beta-3 adrenergic receptors is >9000 times higher than for β1AR or β2AR.4 Vibegron improves clinical symptoms of overactive bladder by increasing bladder capacity without affecting bladder contraction.3 It significantly increases the functional bladder volume in a dose-dependent manner, which results in prolongation of the interval between voids. In clinical studies, vibegron inhibited detrusor bladder contractions in a concentration-dependent manner, reduced voiding pressure, and increased bladder compliance.4 In Japanese clinical studies comprising patients with overactive bladder, vibegron significantly improved the frequency of micturition, urgency, and urgency incontinence episodes.2,4
- Mechanism of action
Overactive bladder is characterized by symptoms of urge urinary incontinence, urgency, and urinary frequency. Bladder filling and emptying are regulated by the coordinated communication between sympathetic and parasympathetic systems. Bladder filling occurs via parasympathetic inhibition and the sympathetic hypogastric nerve releasing norepinephrine, which acts on beta-adrenergic receptors responsible for mediating detrusor muscle relaxation.3,5 Symptoms of overactive bladder are thought to be caused by the deterioration of the sensory connections between the bladder, spinal cord and brain, leading to changes in the lower urinary tract and abnormal bladder sensations of the urge to void at small bladder volumes.4
Beta-3 adrenergic receptors (β3ARs) are expressed in the kidneys and lower urinary tract, including ureters, urethra, prostate, and bladder. Vibegron is a selective agonist at β3AR. One vibegron binds to the receptor, β3AR is stimulated and undergoes a conformation change and activates adenylyl cyclases (AC), which promotes the formation of cyclic adenosine monophosphate (cAMP). Increased intracellular cAMP concentration leads to the activation of cAMP-dependent protein kinase A (PKA), which subsequently phosphorylates myosin light chains that are responsible for inhibiting the interaction of actin with myosin dependent on calcium – calmodulin complex.4,5 In clinical trials, vibegron increased cAMP levels in a dose-proportional manner. There is evidence that β3AR agonists may also work via sensory mechanisms without directly affecting detrusor muscle motor function.4
Target Actions Organism ABeta-3 adrenergic receptor agonistHumans - Absorption
The mean Tmax is 1-3 hours. Steady-state concentrations are achieved within 7 days of once-daily dosing.6
- Volume of distribution
The mean apparent volume of distribution is 6304 L. The average blood-to-plasma concentration ratio is 0.9.6 According to tissue distribution studies in animals, vibegron does not penetrate the blood-brain barrier, suggesting limited potential for CNS toxicity in humans.4
- Protein binding
Vibegron is 49.6–51.3% bound to human plasma proteins.4
- Metabolism
In vitro, CYP3A4 is the main enzyme responsible for the metabolism of vibegron, which plays a minor role in the elimination of vibegron.6 Two predominant metabolic pathways are oxidation and glucuronidation to form two oxidative metabolites and three glucuronide metabolites.4 Metabolites have not been fully characterized.
- Route of elimination
In a radiolabeled drug study, approximately 59% of the radiolabeled dose was recovered in feces, in which 54% of that amount was in the unchanged parent drug form. About 20% of the radioactivity was recovered in urine, in which 19% of the amount was in the unchanged form.6
- Half-life
The terminal plasma half-life ranges from 60 to 70 hours.4 The effective half-life is 30.8 hours.6
- Clearance
There is limited information on the clearance rate of vibegron.
- Adverse Effects
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- Toxicity
There is limited clinical information on overdose from vibegron. In the case of a suspected drug overdose, supportive and symptomatic treatment should be initiated.6
- Affected organisms
- Humans and other mammals
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareDarifenacin Darifenacin may increase the smooth muscle relaxing activities of Vibegron. Digoxin The serum concentration of Digoxin can be increased when it is combined with Vibegron. Fesoterodine Fesoterodine may increase the smooth muscle relaxing activities of Vibegron. Flavoxate Flavoxate may increase the smooth muscle relaxing activities of Vibegron. Mirabegron Mirabegron may increase the smooth muscle relaxing activities of Vibegron. Oxybutynin Oxybutynin may increase the smooth muscle relaxing activities of Vibegron. Propiverine Propiverine may increase the smooth muscle relaxing activities of Vibegron. Solifenacin Solifenacin may increase the smooth muscle relaxing activities of Vibegron. Tolterodine Tolterodine may increase the smooth muscle relaxing activities of Vibegron. Trospium Trospium may increase the smooth muscle relaxing activities of Vibegron. Improve patient outcomesBuild effective decision support tools with the industry’s most comprehensive drug-drug interaction checker.Learn more - Food Interactions
- Take with or without food. A high-fat meal had no clinically significant effects on vibegron plasma concentrations.
Products
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- International/Other Brands
- Beova (Kyorin Pharmaceutical Co., Ltd)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Gemtesa Tablet, film coated 75 mg/1 Oral Urovant Sciences, Inc. 2020-12-29 Not applicable US
Categories
- Drug Categories
- Classification
- Not classified
Chemical Identifiers
- UNII
- M5TSE03W5U
- CAS number
- 1190389-15-1
- InChI Key
- DJXRIQMCROIRCZ-XOEOCAAJSA-N
- InChI
- InChI=1S/C26H28N4O3/c31-24-14-15-27-23-13-12-22(30(23)24)26(33)29-19-8-6-17(7-9-19)16-20-10-11-21(28-20)25(32)18-4-2-1-3-5-18/h1-9,14-15,20-22,25,28,32H,10-13,16H2,(H,29,33)/t20-,21+,22-,25+/m0/s1
- IUPAC Name
- (6S)-N-(4-{[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl}phenyl)-4-oxo-4H,6H,7H,8H-pyrrolo[1,2-a]pyrimidine-6-carboxamide
- SMILES
- [H][C@@]1(CC[C@@H](CC2=CC=C(NC(=O)[C@@H]3CCC4=NC=CC(=O)N34)C=C2)N1)[C@H](O)C1=CC=CC=C1
References
- General References
- Keam SJ: Vibegron: First Global Approval. Drugs. 2018 Nov;78(17):1835-1839. doi: 10.1007/s40265-018-1006-3. [PubMed:30411311]
- Yoshida M, Takeda M, Gotoh M, Yokoyama O, Kakizaki H, Takahashi S, Masumori N, Nagai S, Minemura K: Efficacy of vibegron, a novel beta3-adrenoreceptor agonist, on severe urgency urinary incontinence related to overactive bladder: post hoc analysis of a randomized, placebo-controlled, double-blind, comparative phase 3 study. BJU Int. 2020 May;125(5):709-717. doi: 10.1111/bju.15020. Epub 2020 Feb 23. [PubMed:31991511]
- Di Salvo J, Nagabukuro H, Wickham LA, Abbadie C, DeMartino JA, Fitzmaurice A, Gichuru L, Kulick A, Donnelly MJ, Jochnowitz N, Hurley AL, Pereira A, Sanfiz A, Veronin G, Villa K, Woods J, Zamlynny B, Zycband E, Salituro GM, Frenkl T, Weber AE, Edmondson SD, Struthers M: Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder. J Pharmacol Exp Ther. 2017 Feb;360(2):346-355. doi: 10.1124/jpet.116.237313. Epub 2016 Dec 13. [PubMed:27965369]
- Rechberger T, Wrobel A: Evaluating vibegron for the treatment of overactive bladder. Expert Opin Pharmacother. 2020 Sep 29:1-9. doi: 10.1080/14656566.2020.1809652. [PubMed:32993398]
- Schena G, Caplan MJ: Everything You Always Wanted to Know about beta3-AR * (* But Were Afraid to Ask). Cells. 2019 Apr 16;8(4). pii: cells8040357. doi: 10.3390/cells8040357. [PubMed:30995798]
- FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]
- Drugs.com: FDA Approves Gemtesa [Link]
- External Links
- KEGG Drug
- D10433
- ChemSpider
- 28528047
- BindingDB
- 50146154
- 2472254
- ChEBI
- 142418
- ChEMBL
- CHEMBL2107826
- ZINC
- ZINC000084757336
- Wikipedia
- Vibegron
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Urinary Bladder, Overactive 2 3 Enrolling by Invitation Treatment Urinary Bladder, Overactive 1 3 Recruiting Treatment Urinary Bladder, Overactive 1 2 Completed Treatment Irritable Bowel Syndrome (IBS) 1 2 Completed Treatment Urinary Bladder, Overactive 1 1 Completed Treatment High Blood Pressure (Hypertension) 1 1 Completed Treatment Urinary Bladder, Overactive 2 1 Terminated Treatment Urinary Bladder, Overactive 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 75 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8247415 No 2010-12-01 2030-12-01 US US8653260 No 2009-04-02 2029-04-02 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source logP 2.38 ChemAxon pKa (Strongest Acidic) 12.46 ChemAxon pKa (Strongest Basic) 10.61 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 5 ChemAxon Hydrogen Donor Count 3 ChemAxon Polar Surface Area 94.03 Å2 ChemAxon Rotatable Bond Count 6 ChemAxon Refractivity 126.71 m3·mol-1 ChemAxon Polarizability 47.17 Å3 ChemAxon Number of Rings 5 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
Targets

- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Protein homodimerization activity
- Specific Function
- Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. Beta-3 is involved in the regulation of lipolysis and thermogenesis.
- Gene Name
- ADRB3
- Uniprot ID
- P13945
- Uniprot Name
- Beta-3 adrenergic receptor
- Molecular Weight
- 43518.615 Da
References
- Rechberger T, Wrobel A: Evaluating vibegron for the treatment of overactive bladder. Expert Opin Pharmacother. 2020 Sep 29:1-9. doi: 10.1080/14656566.2020.1809652. [PubMed:32993398]
- FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Vitamin d3 25-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 performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]
Drug created on May 20, 2019 14:33 / Updated on February 21, 2021 18:55