Vibegron

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
Thumb
Weight
Average: 444.535
Monoisotopic: 444.216140778
Chemical Formula
C26H28N4O3
Synonyms
  • Vibegron
  • Vibégron
  • Vibegrón
  • Vibegronum
External IDs
  • KRP-114V
  • MK 4618

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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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
Adverseeffects
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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
DarifenacinDarifenacin may increase the smooth muscle relaxing activities of Vibegron.
DigoxinThe serum concentration of Digoxin can be increased when it is combined with Vibegron.
FesoterodineFesoterodine may increase the smooth muscle relaxing activities of Vibegron.
FlavoxateFlavoxate may increase the smooth muscle relaxing activities of Vibegron.
MirabegronMirabegron may increase the smooth muscle relaxing activities of Vibegron.
OxybutyninOxybutynin may increase the smooth muscle relaxing activities of Vibegron.
PropiverinePropiverine may increase the smooth muscle relaxing activities of Vibegron.
SolifenacinSolifenacin may increase the smooth muscle relaxing activities of Vibegron.
TolterodineTolterodine may increase the smooth muscle relaxing activities of Vibegron.
TrospiumTrospium may increase the smooth muscle relaxing activities of Vibegron.
Interactions
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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/1OralUrovant Sciences, Inc.2020-12-29Not applicableUS flag

Categories

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
PhaseStatusPurposeConditionsCount
4Not Yet RecruitingTreatmentOveractive Bladder Syndrome (OABS)1
3CompletedTreatmentOveractive Bladder Syndrome (OABS)2
3Enrolling by InvitationTreatmentOveractive Bladder Syndrome (OABS)1
3RecruitingTreatmentOveractive Bladder Syndrome (OABS)1
2CompletedTreatmentIrritable Bowel Syndrome (IBS)1
2CompletedTreatmentOveractive Bladder Syndrome (OABS)1
1CompletedTreatmentHigh Blood Pressure (Hypertension)1
1CompletedTreatmentOveractive Bladder Syndrome (OABS)2
1TerminatedTreatmentOveractive Bladder Syndrome (OABS)1

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
Not Available

Targets

Drugtargets2
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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
  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. 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
  1. 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
  1. FDA Approved Drug Products: GEMTESA (vibegron) tablets, for oral use [Link]

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