Vedolizumab

Identification

Summary

Vedolizumab is an integrin blocker and anti-inflammatory agent used to manage ulcerative colitis and Crohn's disease in adults.

Brand Names
Entyvio
Generic Name
Vedolizumab
DrugBank Accession Number
DB09033
Background

Vedolizumab is a recombinant humanized IgG1 monoclonal antibody directed against the human lymphocyte α4β7 integrin, a key mediator of gastrointestinal inflammation implicated in diseases like ulcerative colitis or Crohn's disease.4 α4β7 integrin facilitates the interaction between lymphocytes and gut endothelial cells through the α4β7 integrin-MAdCAM1 interaction, leading to the mobilization of lymphocytes and thus contributing to gastrointestinal inflammation.4 Integrins implicated in cell migration into the intestinal tract included α2β2, α4β1, and α4β7; however, the selective activity of vedolizumab against α4β7 integrin has been thought to contribute to its more favorable safety profile compared to its predecessor natalizumab, the first integrin receptor antagonist approved by the FDA.3 Vedolizumab is administered by IV infusion over a period of 30 minutes; after the first dose, it is given again at two and six weeks and then every 8 weeks thereafter.4

Vedolizumab was developed by Takeda and approved by the FDA under the brand name ENTYVIO for the maintenance therapy of moderately to severely active Ulcerative Colitis and Crohn’s Disease in April and September 2023, respectively.6,7

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Protein Chemical Formula
C6528H10072N1732O2042S42
Protein Average Weight
146837.0 Da
Sequences
>Heavy Chain Sequence
QVQLVQSGAEVKKPGASVKVSCKGSGYTFTSYWMHWVRQAPGQRLEWIGEIDPSESNTNY
NQKFKGRVTLTVDISASTAYMELSSLRSEDTAVYYCARGGYDGWDYAIDYWGQGTLVTVS
SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAG
APSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>Light Chain Sequence
DVVMTQSPLSLPVTPGEPASISCRSSQSLAKSYGNTYLSWYLQKPGQSPQLLIYGISNRF
SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQPYTFGQGTKVEIKRTVAAPSV
FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Download FASTA Format
Synonyms
  • Vedolizumab
External IDs
  • LDP 02
  • LDP-02
  • LDP02
  • MLN-0002
  • MLN-02
  • MLN0002
  • MLN02

Pharmacology

Indication

Vedolizumab is indicated for adult patients with moderately to severely active Ulcerative Colitis or Crohn’s disease.4

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofModerately to severely active crohn's disease•••••••••••••••••••••
Treatment ofModerately to severely active ulcerative colitis•••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Non-clinical studies have shown that the pharmacodynamic effects of vedolizumab are reversible upon removal of the antibody: pharmacologic activity of cells inhibited by vedolizumab could be partially restored within 24 hours after removal, with near complete restoration within 4 days. There are no known drug interactions as vedolizumab is a humanized antibody and does not modulate the production of cytokines, which is known to affect drug metabolism.5

The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is mainly expressed on gut endothelial cells and plays a critical role in homing T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to chronic inflammation, a hallmark of ulcerative colitis and Crohn’s disease. Inhibition of α4β7 integrin by vedolizumab prevents the adhesion of lymphocytes to its natural ligand, thus decreasing the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue.4

In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg (which includes doses outside of the recommended dose), saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut-immune surveillance was observed.4

In clinical trials with vedolizumab at doses ranging from 0.2 to 10 mg/kg and 180 to 750 mg (which include doses outside of the recommended dose) in healthy subjects and in patients with ulcerative colitis or Crohn’s disease, vedolizumab did not elevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T-lymphocytes, total memory helper T-lymphocytes, monocytes or natural killer cells.4

A reduction in gastrointestinal inflammation was observed in rectal biopsy specimens from Phase 2 ulcerative colitis patients exposed to vedolizumab for four or six weeks compared to placebo control as assessed by histopathology.4

In a study of 14 healthy subjects, vedolizumab did not affect the CD4+ lymphocyte cell counts, CD8+ lymphocyte cell counts, or the CD4+:CD8+ ratios in the CSF.4

Mechanism of action

Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with MAdCAM-1. Vedolizumab does not bind to or inhibit the function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1).4

TargetActionsOrganism
AIntegrin alpha-4
antibody
Humans
AIntegrin beta-7
antibody
Humans
Absorption

The intended route of administration is intravenous, therefore there is no absorption data and bioavailability is expected to be 100%. Following the administration of 300 mg of vedolizumab as a 30-minute intravenous infusion from week 0 to 2 and 300 mg every eight weeks starting from Week 6, the trough serum concentration of vedolizumab is 26.3 ± 12.9 and 27.4 ± 19.2 mcg/mL for Ulcerative Colitis and Crohn’s Disease patients respectively at week 6.5 At week 46, the trough serum concentration of vedolizumab is 11.2 ± 7.2 and 13.0 ± 9.1 mcg/mL for Ulcerative Colitis and Crohn’s Disease patients respectively.5

Volume of distribution

Serum apparent volume of distribution at steady-state has been found to be moderately greater than the serum volume (approximately 5L).4,5 It is therefore expected to be confined to the systemic circulation, as expected for a high molecular weight protein.5

Protein binding

Vedolizumab is a therapeutic monoclonal antibody and is not expected to bind to plasma proteins.5

Metabolism

The expected consequence of metabolism is proteolytic degradation to small peptides and individual amino acids, and receptor-mediated clearance.5

Route of elimination

Renal clearance is negligible as vedolizumab is a high molecular weight protein.

Half-life

Vedolizumab has a long terminal elimination half-life of 25 days.4,5

Clearance

Vedolizumab clearance depends on both linear and nonlinear pathways; the nonlinear clearance decreases with increasing concentrations. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day or 0.180 to 0.266 ml/hr/kg.4,5

Adverse Effects
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Toxicity

Elevated transaminase levels with or without elevated bilirubin have occurred in patients who have received this drug. Progressive multifocal leukoencephalopathy (PML) has not been reported with the use of this drug, however, it has occurred in patients who have received different integrin receptor antagonists and is therefore considered a risk for this product.4 The use of vedolizumab may increase the risk of developing infections, and one study found that nasopharyngitis occurs more frequently with vedolizumab than with THE placebo for Crohn’s disease patients.2

Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified a vedolizumab-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy. No fetal harm was observed in animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage.4

Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth.4

Vedolizumab administered during pregnancy could affect immune responses in the in-utero-exposed newborn and infant. The clinical significance of low levels of vedolizumab in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown.4

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of vedolizumab. Studies to evaluate the possible impairment of fertility or mutagenic potential of vedolizumab have not been performed.4

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
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Vedolizumab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Vedolizumab.
AdalimumabThe risk or severity of infection can be increased when Adalimumab is combined with Vedolizumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Vedolizumab.
AducanumabThe risk or severity of adverse effects can be increased when Vedolizumab is combined with Aducanumab.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EntyvioInjection, solution108 mgSubcutaneousTakeda Pharma A/S2021-02-10Not applicableEU flag
EntyvioPowder, for solution300 mg / vialIntravenousTakeda2015-04-21Not applicableCanada flag
EntyvioInjection, solution108 mgSubcutaneousTakeda Pharma A/S2021-02-10Not applicableEU flag
EntyvioInjection, solution108 mgSubcutaneousTakeda Pharma A/S2021-02-10Not applicableEU flag
EntyvioSolution108 mg / 0.68 mLSubcutaneousTakeda2020-07-08Not applicableCanada flag

Categories

ATC Codes
L04AG05 — Vedolizumab
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
9RV78Q2002
CAS number
943609-66-3

References

General References
  1. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER: The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009 Sep;330(3):864-75. doi: 10.1124/jpet.109.153973. Epub 2009 Jun 9. [Article]
  2. Wang MC, Zhang LY, Han W, Shao Y, Chen M, Ni R, Wang GN, Wei FX, Zhang YW, Xu XD, Zhang YC: PRISMA--efficacy and safety of vedolizumab for inflammatory bowel diseases: a systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2014 Dec;93(28):e326. doi: 10.1097/MD.0000000000000326. [Article]
  3. Cherry LN, Yunker NS, Lambert ER, Vaughan D, Lowe DK: Vedolizumab: an alpha4beta7 integrin antagonist for ulcerative colitis and Crohn's disease. Ther Adv Chronic Dis. 2015 Sep;6(5):224-33. doi: 10.1177/2040622315586970. [Article]
  4. FDA Approved Drug Products: ENTYVIO (vedolizumab) for injection, for intravenous use [Link]
  5. Assessment report: Entyvio (International non-proprietary name vedolizumab) [Link]
  6. Takeda Announces FDA Acceptance of BLA Resubmission for Investigational Subcutaneous Administration of Entyvio® (vedolizumab) for Maintenance Therapy in Moderately to Severely Active Ulcerative Colitis [Link]
  7. Takeda Announces FDA Acceptance of BLA for Subcutaneous Administration of ENTYVIO® (vedolizumab) for Maintenance Therapy in Moderately to Severely Active Crohn’s Disease [Link]
KEGG Drug
D08083
PubChem Substance
347910392
RxNav
1538097
ChEMBL
CHEMBL1743087
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Vedolizumab
FDA label
Download (281 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
4Active Not RecruitingTreatmentCrohn Disease of Small Intestine1somestatusstop reasonjust information to hide
4Active Not RecruitingTreatmentUlcerative Colitis1somestatusstop reasonjust information to hide
4CompletedTreatmentCrohn's Disease (CD)3somestatusstop reasonjust information to hide
4CompletedTreatmentCrohn's Disease (CD) / Ulcerative Colitis2somestatusstop reasonjust information to hide
4CompletedTreatmentPouchitis1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous
Injection, powder, for solutionIntravenous33100000 mg
Injection, powder, for solutionIntravenous; Parenteral300 MG
Injection, powder, lyophilized, for solutionIntravenous300 mg/5mL
Injection, solutionSubcutaneous108 MG
Powder, for solutionIntravenous300 mg / vial
SolutionIntravenous300.000 mg
SolutionSubcutaneous108 mg / 0.68 mL
PowderIntravenous300 mg
Injection, powder, lyophilized, for solutionIntravenous
Injection, solutionSubcutaneous108 mg/0.68mL
Injection, powder, for solutionIntravenous300 mg
SolutionSubcutaneous108.00 mg
SolutionSubcutaneous10800000 mg
SolutionSubcutaneous108 mg
Injection, solution, concentrateIntravenous300 mg/1vial
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US2012151248No2012-05-022032-05-02US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
isoelectric point7.6-8.3European Medicines Agency Assessment Report (Procedure No.: EMEA/H/C/002782/0000)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Metal ion binding
Specific Function
Integrins alpha-4/beta-1 (VLA-4) and alpha-4/beta-7 are receptors for fibronectin. They recognize one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. They are...
Gene Name
ITGA4
Uniprot ID
P13612
Uniprot Name
Integrin alpha-4
Molecular Weight
114898.745 Da
References
  1. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER: The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009 Sep;330(3):864-75. doi: 10.1124/jpet.109.153973. Epub 2009 Jun 9. [Article]
  2. FDA Approved Drug Products: ENTYVIO (vedolizumab) for injection, for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Virus receptor activity
Specific Function
Integrin alpha-4/beta-7 (Peyer patches-specific homing receptor LPAM-1) is an adhesion molecule that mediates lymphocyte migration and homing to gut-associated lymphoid tissue (GALT). Integrin alph...
Gene Name
ITGB7
Uniprot ID
P26010
Uniprot Name
Integrin beta-7
Molecular Weight
86902.415 Da
References
  1. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER: The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009 Sep;330(3):864-75. doi: 10.1124/jpet.109.153973. Epub 2009 Jun 9. [Article]
  2. FDA Approved Drug Products: ENTYVIO (vedolizumab) for injection, for intravenous use [Link]

Drug created at February 20, 2015 22:30 / Updated at November 24, 2023 04:34