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Vibegron

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Identification

Summary

Vibegron is a beta-3 adrenergic agonist the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults.

Brand Names
Gemtesa
Generic Name
Vibegron
DrugBank Accession Number
DB14895
Background

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
3D
Similar Structures
Weight
Average: 444.535
Monoisotopic: 444.216140778
Chemical Formula
C26H28N4O3
Synonyms
  • Vibegron
  • Vibégron
  • Vibegrón
  • Vibegronum
External IDs
  • KRP-114V
  • MK 4618
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Pharmacology

Indication

Vibegron is indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults.6

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofUrinary bladder, overactive•••••••••••••••••••••••
Contraindications & Blackbox Warnings
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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

TargetActionsOrganism
ABeta-3 adrenergic receptor
agonist
Humans
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

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
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interactions in your software
AcebutololThe therapeutic efficacy of Vibegron can be decreased when used in combination with Acebutolol.
AlfuzosinThe therapeutic efficacy of Vibegron can be decreased when used in combination with Alfuzosin.
AmitriptylineThe therapeutic efficacy of Vibegron can be decreased when used in combination with Amitriptyline.
AmitriptylinoxideThe risk or severity of hypertension can be increased when Amitriptylinoxide is combined with Vibegron.
AmoxapineThe therapeutic efficacy of Vibegron can be decreased when used in combination with Amoxapine.
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
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
GemtesaTablet, film coated75 mg/1OralSumitomo Pharma America, Inc.2020-12-29Not applicableUS flag

Categories

ATC Codes
G04BD15 — Vibegron
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

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
  1. Keam SJ: Vibegron: First Global Approval. Drugs. 2018 Nov;78(17):1835-1839. doi: 10.1007/s40265-018-1006-3. [Article]
  2. 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. [Article]
  3. 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. [Article]
  4. 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. [Article]
  5. 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. [Article]
  6. FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]
  7. Drugs.com: FDA Approves Gemtesa [Link]
KEGG Drug
D10433
ChemSpider
28528047
BindingDB
50146154
RxNav
2472254
ChEBI
142418
ChEMBL
CHEMBL2107826
ZINC
ZINC000084757336
Wikipedia
Vibegron

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
4RecruitingTreatmentUrinary Urgency Incontinence1somestatusstop reasonjust information to hide
3CompletedTreatmentOveractive Bladder Syndrome (OABS)4somestatusstop reasonjust information to hide
2CompletedTreatmentIrritable Bowel Syndrome (IBS)1somestatusstop reasonjust information to hide
2CompletedTreatmentOveractive Bladder Syndrome (OABS)1somestatusstop reasonjust information to hide
2, 3RecruitingTreatmentNeurogenic Detrusor Overactivity1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral75 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8247415No2012-08-212030-12-01US flag
US8653260No2014-02-182029-04-02US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP2.38Chemaxon
pKa (Strongest Acidic)12.46Chemaxon
pKa (Strongest Basic)10.61Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area94.03 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity126.71 m3·mol-1Chemaxon
Polarizability47.17 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
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/MSsplash10-01ot-0500900000-8c15dbdcd8246a4d24ba
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-052o-1905700000-40e54c85ae5a581361ff
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-004j-2201900000-7eb1375e6c3721433f07
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-052o-4669700000-5d8814cf7e8941262862
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-000m-1921200000-3d861ef9e6fbc73b4906
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-4793300000-96bba31096249754f04c
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details1. Beta-3 adrenergic receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General 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
Specific Function
Beta-3 adrenergic receptor binding
Gene Name
ADRB3
Uniprot ID
P13945
Uniprot Name
Beta-3 adrenergic receptor
Molecular Weight
43518.615 Da
References
  1. 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. [Article]
  2. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
  3. FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]

Transporters

Details1. ATP-dependent translocase ABCB1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function
Abc-type xenobiotic transporter activity
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
ATP-dependent translocase ABCB1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]

Drug created at May 20, 2019 14:33 / Updated at August 13, 2021 04:44