Vedolizumab

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Vedolizumab Drug Information

Pharmacodynamics

Network Meta Analyses

Drug Drug Interactions

Pharmacokinetics

Therapeutic Drug Monitoring

Vedolizumab Pharmacodynamics

Vedolizumab is a gut-selective humanized monoclonal antibody that specifically binds to the α4β7 integrin, blocking its interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thereby inhibiting the migration of gut-homing T lymphocytes into intestinal tissue and reducing inflammation in IBD

Molecular Mechanism:

Target Specificity

Humanized IgG1 monoclonal antibody
Selectively binds α4β7 integrin on lymphocytes
Binding affinity: Kd ≈ 0.04-0.1 nM
Does not bind to α4β1 or αEβ7 integrins

Tissue-Specific Actions

Primary site: Gut-associated lymphoid tissue (GALT)
Blocks interaction with MAdCAM-1 on intestinal vasculature
MAdCAM-1 expression highest in:
- Small intestine
- Colon
- Peyer's patches
- Mesenteric lymph nodes

Cellular Effects:

Lymphocyte Trafficking
Prevents adhesion to intestinal vasculature
Blocks transmigration into inflamed tissue
Affects mainly memory T-cells

Immunological Impact

No effect on systemic immune responses
Preserves:
- CNS immune surveillance (unlike natalizumab)
- Peripheral immune function
- Vaccination responses
- Memory B-cell populations

Pharmacodynamic Parameters:

Receptor Saturation

Maximum effect at >90% α4β7 saturation
Sustained saturation requires trough levels >10 μg/mL
Receptor occupancy correlates with serum concentrations

Temporal Dynamics

Onset of action:
- Initial effects: Days (cellular level)
- Clinical response: 6-10 weeks
- Full effect: Up to 14 weeks
Duration of action:
- Maintains effect throughout dosing interval
- Effects persist 16+ weeks after last dose
Recovery period:
- Lymphocyte trafficking normalizes as drug clears
- Complete reversal typically within 16-24 weeks

Clinical Biomarkers:

Monitoring Parameters

Serum drug concentrations
α4β7 receptor saturation
Fecal calprotectin
C-reactive protein

Response Indicators

Mucosal healing
Reduced inflammatory markers
Decreased lymphocyte counts in intestinal tissue
Clinical symptom improvement

Resistance Mechanisms:

Primary Non-response

Inadequate receptor saturation
Alternative inflammatory pathways
Pre-existing tissue damage

Secondary Loss of Response

Anti-drug antibodies (uncommon)
Disease severity changes
Alternative pathways becoming dominant

Vedolizumab Pharmacokinetics

Vedolizumab exhibits linear pharmacokinetics with a half-life of approximately 25 days, undergoes proteolytic degradation rather than hepatic metabolism, has limited distribution primarily to the vascular and extravascular spaces, and achieves steady-state concentrations by week 6 with dose-proportional exposure following intravenous administration.

Absorption & Distribution

Administered via intravenous infusion
Initial doses: Weeks 0, 2, and 6
Maintenance: Every 8 weeks
Volume of distribution: ~5 liters
Distribution primarily in vascular compartment

Mechanism

Humanized monoclonal IgG1 antibody
Targets α4β7 integrin
Selective gut-homing antagonist
Prevents lymphocyte trafficking to intestinal tissue

Key Pharmacokinetic Parameters

Half-life: approximately 25 days
Clearance: ~0.157 L/day
Steady state reached by week 6
Linear elimination at therapeutic concentrations

Factors Affecting Pharmacokinetics

a) Patient-specific:

Body weight
Serum albumin levels
Presence of anti-vedolizumab antibodies
Disease severity
Prior TNF antagonist exposure

b) Disease-related:

High inflammatory burden
Low albumin levels
Development of anti-drug antibodies

Special Populations

No significant differences based on:
- Age
- Gender
- Race
No formal studies in:
- Pediatric patients
- Renal impairment
- Hepatic impairment

Drug Monitoring

Trough concentrations correlate with efficacy
Target trough levels: >10 μg/mL
Monitoring recommended in:
- Loss of response
- Primary non-response
- Before dose adjustment

Drug-Drug Interactions

Limited interactions due to:
- Targeted mechanism
- Limited systemic exposure
- Minimal metabolism
Can be used with:
- Aminosalicylates
- Corticosteroids
- Immunomodulators

Elimination

Proteolytic degradation
Catabolized throughout body
No specific organ elimination
No dose adjustment needed for organ dysfunction

Vedolizumab Pivotal Studies

Vedolizumab demonstrated efficacy in IBD through the GEMINI trials, with GEMINI 1 establishing its effectiveness for ulcerative colitis and GEMINI 2 and 3 confirming its benefits for Crohn's disease, all showing superiority to placebo for induction and maintenance of clinical remission.

GEMINI 2 (Key Phase 3 Trial) Design:

Randomized, double-blind, placebo-controlled

368 patients in induction phase
461 patients in maintenance phase
Duration: 52 weeks
Results: Induction (Week 6):
Clinical remission: 14.5% vedolizumab vs 6.8% placebo (p=0.02)
CDAI-100 response: 31.4% vedolizumab vs 25.7% placebo (p=0.23)

Maintenance (Week 52):

Clinical remission:
Q8W: 39.0%
Q4W: 36.4%
Placebo: 21.6%
(p<0.001 for both regimens)

GEMINI 3 Design:

Focused on TNF-antagonist failures
416 patients randomized
Primary endpoint at week 6
Extended induction assessment at week 10

Results: Week 6 (TNF-failure population):

Clinical remission: 15.2% vedolizumab vs 12.1% placebo (p=0.433)

Week 10:

Clinical remission: 26.6% vedolizumab vs 12.1% placebo (p=0.001)

Key Secondary Outcomes (Combined Studies)

Corticosteroid-free remission
Mucosal healing
Quality of life improvements
Safety profile

Safety Data: Common adverse events:

Nasopharyngitis
Headache
Arthralgia
Upper respiratory tract infections

No increased risk of:

Serious infections
Progressive multifocal leukoencephalopathy
Malignancy

Subgroup Analyses:

Better responses in:

TNF-naïve patients
Earlier disease
Lower inflammatory burden
No prior surgery

Follow-up Real-World Studies VICTORY Consortium:

Cumulative rates:
- Clinical remission: 35% at 6 months
- Steroid-free remission: 45% at 12 months
- Endoscopic healing: 63% at 12 months

Important Clinical Implications:

More effective in TNF-naïve patients
Better outcomes with early treatment
Extended induction may benefit some patients
Q8W maintenance generally sufficient
Safe long-term treatment option

Vedolizumab Network Meta Analyses and Head to Head

Vedolizumab has been compared to other biologics through network meta-analyses suggesting comparable efficacy to anti-TNFs in ulcerative colitis and Crohn's disease, while the VARSITY trial provided direct evidence of its superiority over adalimumab for clinical remission in moderate-to-severe ulcerative colitis.

Ulcerative Colitis NMAs:

Singh et al. (2020) Systematic Review and Network Meta-analysis:

Included 21 trials
Induction of clinical remission:
- Vedolizumab comparable to infliximab and adalimumab
- All biologics superior to placebo
Mucosal healing rates:
- Vedolizumab showed comparable or slightly better rates vs TNF inhibitors
- OR vs placebo approximately 2.5-3.0

Danese et al. NMA:

Safety outcomes focus
Lower rates of serious infections vs TNF inhibitors
Similar rates of adverse events leading to discontinuation
Lower immunogenicity compared to TNF inhibitors

Crohn's Disease NMAs:

Singh et al. (2018) Network Meta-analysis:

Included 15 RCTs
Induction outcomes:
- Slightly lower efficacy vs adalimumab/infliximab for clinical remission
- Comparable rates of clinical response

- Maintenance phase:
  - Similar sustained clinical remission rates
  - Better long-term safety profile

Pagnini et al. NMA:

Focus on real-world effectiveness
Included observational studies
Key findings:
- Comparable effectiveness for bio-naive patients
- Better performance in TNF-failure patients vs second TNF inhibitor
- Lower serious infection rates

Methodological Considerations:

Most NMAs had moderate to high heterogeneity
Variable definitions of endpoints across included studies
Different timepoints for outcome assessment
Limited long-term comparative data

VARSITY Trial (UC) Head to Head Trial

Design: Phase 3b, double-blind, double-dummy, multicenter RCT
Population: 769 moderate-severe UC patients (bio-naive)
Comparison: Vedolizumab IV vs Adalimumab SC
Duration: 52 weeks

Key Results:

Primary Endpoint:

Clinical remission at week 52
- Vedolizumab: 31.3%
- Adalimumab: 22.5%
- Difference: 8.8% (95% CI: 2.5-15.0), p=0.006

Secondary Endpoints:

Endoscopic improvement at week 52:
- Vedolizumab: 39.7%
- Adalimumab: 27.7%
- Difference: 12.0% (95% CI: 5.3-18.7), p<0.001
Corticosteroid-free remission:
- Vedolizumab: 12.6%
- Adalimumab: 21.8%
- Difference not statistically significant

Vedolizumab Drug Moniotring

Vedolizumab therapeutic drug monitoring measures serum drug concentrations with higher trough levels (>11-14 μg/mL induction, >12-13 μg/mL maintenance) associated with improved outcomes, though standardized therapeutic ranges and routine proactive monitoring are not yet firmly established in clinical practice.

Trough Levels:

Proposed Target Ranges:

Induction phase: >20-25 μg/mL
Maintenance phase: >10-14 μg/mL
Variations exist between UC and CD

Key Time Points:

Week 6 (early indicator)
Week 14 (end of induction)
During maintenance (routine monitoring)

Clinical Correlations:

UC:

Higher trough levels associated with:
- Better clinical remission rates
- Improved mucosal healing
- Week 6 levels predictive of week 14 outcomes

CD:

Less clear correlation than UC

Higher variability in target levels
May need higher concentrations than UC

Factors Affecting Levels:

Patient Characteristics:

Body weight
Albumin levels
Disease severity
Prior biologics exposure

Disease-Related:

High inflammatory burden
Low albumin
Protein loss
Disease location/extent

Immunogenicity:

Anti-Drug Antibodies (ADA):

Low immunogenicity (2-4%)
Usually transient
Lower than TNF inhibitors
Impact on efficacy unclear

Practical Applications:

When to Check:

Proactive monitoring debated
Reactive testing for loss of response
Early monitoring may predict outcomes

Dose Optimization:

Q8W to Q4W based on levels
Limited data on exact thresholds
Individual target ranges may vary

Vedolizumab Adverse Effects

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Vedolizumab has a favorable safety profile characterized by low rates of infusion reactions, minimal serious infections due to gut selectivity, rare cases of progressive multifocal leukoencephalopathy, and occasional nasopharyngitis, headache, arthralgia, and nausea as the most common adverse events.

Common Adverse Effects (>1%):

Infections

Nasopharyngitis (13-14%)
Upper respiratory tract infections (7-8%)
Bronchitis (3-4%)
Sinusitis (3%)
Influenza (3%)

Gastrointestinal

Nausea (3-4%)
Abdominal pain (3%)
Upper abdominal pain (2%)

Musculoskeletal

Arthralgia (5-6%)
Back pain (3-4%)
Myalgia (2%)

Other

Headache (9-12%)
Fatigue (3-4%)
Pyrexia (2-3%)

Serious Adverse Effects:

Infections

Serious infections (<2%)
C. difficile infection (rare)
No increased TB risk observed
Low rates of opportunistic infections

Immunologic

Infusion reactions (4%)
Serious hypersensitivity (<1%)
Anti-drug antibodies (3-4%)

Special Populations/Considerations:

Pregnancy

Category B
Low placental transfer
Growing evidence for safety in pregnancy

Malignancy

No increased risk observed
Monitoring recommended as per standard practice

Surgery

No clear increased post-operative complications
Consider timing relative to dosing

Comparative Safety Profile:

Lower infection rates vs TNF inhibitors
Lower immunogenicity vs TNF inhibitors
No observed demyelination risk
No observed increased cardiovascular risk

Vedolizumab Drug Interactions

Vedolizumab has minimal drug interactions due to its gut-selective mechanism and lack of hepatic metabolism, allowing concurrent administration with immunomodulators, corticosteroids, and most medications without significant pharmacokinetic interference.

Key Characteristics:

Target-specific gut-selective mechanism
Minimal systemic absorption
Low potential for CYP450 interactions
Limited drug-drug interaction profile

Documented Interactions:

Immunosuppressants:

Can be used with thiopurines
Safe with methotrexate
No increased risk when combined
No dose adjustments needed

Corticosteroids:

No significant interactions
Can be used concurrently
Useful for induction bridging
No dose adjustments required

Biologics:

Avoid concurrent use
Washout period recommended
No formal interaction studies
Increased immunosuppression risk

Notable Non-Interactions:

Common IBD Medications:

5-ASA compounds
Antibiotics
Antidiarrheals
Probiotics

Other Medications:

No effect on vaccine responses (except live vaccines)
No interaction with oral contraceptives
No effect on common medications metabolized by CYP450

Clinical Considerations:

Vaccination:

Avoid live vaccines during treatment
Non-live vaccines safe
Consider timing with dosing
Monitor vaccine response

Surgery:

No specific drug interactions affecting surgery
Consider timing of last dose
No interaction with anesthetics

Vedolizumab in Pregnancy

Vedolizumab is considered low-risk in pregnancy with minimal placental transfer during the first two trimesters, although transfer increases in the third trimester, and current data from pregnancy registries suggests no increased risk of adverse pregnancy outcomes or congenital abnormalities.

Current Evidence:

Safety Classification:

Pregnancy Category B
Low risk classification
Limited placental transfer in late pregnancy
IgG1 monoclonal antibody

Key Studies:

CONCEIVE study (European prospective)
US PIANO registry data
Post-marketing surveillance

Pregnancy Outcomes:

Mother:

No increased adverse events
Disease control maintained
Similar flare rates to non-pregnant
No new safety signals

Fetus/Newborn:

No increased congenital anomalies
Normal birth weights
Term deliveries comparable
No specific pattern of defects

Clinical Recommendations:

Pre-conception:
Continue if disease control needed
No mandatory washout
Discuss benefit/risk

During Pregnancy:

Can continue throughout
Monitor disease activity
Regular obstetric care
No dose adjustments needed

Third Trimester:

Consider timing of last dose

Low placental transfer
Individual risk/benefit assessment
Disease activity key factor

Moens A, van der Woude CJ, Julsgaard M, et al. Pregnancy outcomes in inflammatory bowel disease patients treated with vedolizumab, anti-TNF or conventional therapy: results of the European CONCEIVE study. Aliment Pharmacol Ther. 2020; 51: 129–138. https://doi.org/10.1111/apt.15539

Study Design:

Multicenter, prospective, observational cohort study
European centers (ECCO-EpiCom)
Three treatment groups:
- Vedolizumab
- Anti-TNF
- Conventional therapy

Key Results:

Pregnancy Outcomes:

Live births:
- Vedolizumab: comparable to other groups
- No significant difference in birth rates
Birth weight and gestational age: similar across groups

Adverse Pregnancy Outcomes:

Spontaneous abortions
Congenital abnormalities
No significant differences between treatment groups

Disease Activity:

Disease control during pregnancy
Flare rates similar between groups
No increased risk with vedolizumab

Safety Profile:

No new safety signals
Comparable to anti-TNF agents
No increased risk of adverse outcomes

Study Limitations:

Observational design
Potential selection bias
Limited sample size in vedolizumab group

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Vedolizumab General References

Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

Sands BE, Feagan BG, Rutgeerts P, et al. Effects of Vedolizumab Induction Therapy for Patients With Crohn's Disease in Whom Tumor Necrosis Factor Antagonist Treatment Failed. Gastroenterology. 2014;147(3):618-627.e3.

Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2013;369(8):699-710.

Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. N Engl J Med. 2019;381(13):1215-1226.

Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review with network meta-analysis: first- and second-line pharmacotherapy for moderate-severe ulcerative colitis. Aliment Pharmacol Ther. 2018;47(2):162-175.

Moens A, van der Woude CJ, Julsgaard M, et al. Pregnancy outcomes in inflammatory bowel disease patients treated with vedolizumab, anti-TNF or conventional therapy: results of the European CONCEIVE study. Aliment Pharmacol Ther. 2020; 51: 129–138. https://doi.org/10.1111/apt.15539