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Vedolizumab

Introduction to Vedolizumab

Vedolizumab (Entyvio) is a humanized monoclonal antibody developed by Takeda Pharmaceuticals for the treatment of inflammatory bowel diseases (IBD). It was approved by the FDA in 2014 for adult patients with moderate to severe ulcerative colitis (UC) and Crohn's disease (CD) who have had an inadequate response to, lost response to, or were intolerant to conventional therapy or a tumor necrosis factor (TNF) antagonist.

Mechanism of Action

Vedolizumab is a gut-selective integrin antagonist. It specifically binds to the α4β7 integrin, a protein on the surface of certain white blood cells. This binding inhibits the adhesion of these cells to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is mainly expressed on gut endothelial cells. By blocking this interaction, vedolizumab reduces inflammation in the gastrointestinal tract without affecting systemic immune responses.

Key points:

  • Targets α4β7 integrin on lymphocytes
  • Prevents binding to MAdCAM-1 on intestinal vasculature
  • Reduces lymphocyte trafficking to the gut
  • Gut-selective action minimizes systemic immunosuppression

Indications

Vedolizumab is indicated for:

  1. Ulcerative Colitis (UC):
    • Adult patients with moderately to severely active UC
    • Patients who have had an inadequate response with, lost response to, or were intolerant to:
      • A tumor necrosis factor (TNF) blocker
      • An immunomodulator
      • Corticosteroid treatment
  2. Crohn's Disease (CD):
    • Adult patients with moderately to severely active CD
    • Patients who have had an inadequate response with, lost response to, or were intolerant to:
      • A tumor necrosis factor (TNF) blocker
      • An immunomodulator
      • Corticosteroid treatment

Pharmacokinetics

Understanding the pharmacokinetics of vedolizumab is crucial for optimal dosing and therapeutic management:

  • Distribution: Primarily restricted to the gut due to its targeted mechanism of action
  • Half-life: Approximately 25 days
  • Clearance: 0.157 L/day
  • Volume of distribution: 5.12 L
  • Metabolism: As a monoclonal antibody, it is catabolized into peptides and amino acids
  • Elimination: Not expected to undergo renal elimination or hepatic metabolism

Steady-state concentrations are usually achieved by week 6 following every 8-week dosing regimens.

Dosage and Administration

Vedolizumab is administered as an intravenous infusion. The recommended dosage regimen is:

  1. Induction phase:
    • 300 mg at 0, 2, and 6 weeks
  2. Maintenance phase:
    • 300 mg every 8 weeks

Important administration details:

  • Infuse over 30 minutes
  • Do not administer as an intravenous push or bolus
  • Patients should be monitored during infusion and for at least two hours after completion of infusion

Dose adjustment may be necessary based on clinical response. Some patients, particularly those with Crohn's disease, may benefit from dose intensification to 300 mg every 4 weeks if they have had an inadequate response.

Clinical Efficacy

Vedolizumab has demonstrated efficacy in several large-scale clinical trials:

  1. Ulcerative Colitis:
    • GEMINI I trial: Significantly higher rates of clinical response, clinical remission, and mucosal healing compared to placebo at week 6 and week 52
    • Induction response rates: 47.1% (vedolizumab) vs. 25.5% (placebo)
    • Maintenance remission rates at week 52: 41.8% (vedolizumab every 8 weeks) vs. 15.9% (placebo)
  2. Crohn's Disease:
    • GEMINI II and III trials: Demonstrated efficacy in inducing clinical remission and response
    • Induction remission rates at week 6: 14.5% (vedolizumab) vs. 6.8% (placebo)
    • Maintenance remission rates at week 52: 39% (vedolizumab every 8 weeks) vs. 21.6% (placebo)

Long-term follow-up studies have shown sustained efficacy and safety profile with continued use of vedolizumab for up to 5 years.

Side Effects

Vedolizumab is generally well-tolerated, but like all medications, it can cause side effects. Common adverse reactions include:

  • Nasopharyngitis (13%)
  • Headache (12%)
  • Arthralgia (12%)
  • Nausea (9%)
  • Pyrexia (9%)
  • Upper respiratory tract infection (7%)
  • Fatigue (6%)
  • Cough (5%)

Serious adverse reactions reported in clinical studies include:

  • Infections (e.g., anal abscess, sepsis, tuberculosis)
  • Liver injury
  • Infusion-related reactions and hypersensitivity

The gut-selective mechanism of vedolizumab may contribute to a lower risk of systemic adverse events compared to other biologic therapies used in IBD.

Precautions and Contraindications

Contraindications:

  • Known serious or severe hypersensitivity reaction to vedolizumab or any of its excipients

Precautions:

  • Infections: Patients should be screened for tuberculosis and other infections before starting treatment. Vedolizumab should be discontinued if serious infection occurs.
  • Progressive Multifocal Leukoencephalopathy (PML): While no cases have been reported with vedolizumab use, patients should be monitored for new or worsening neurological signs and symptoms.
  • Liver Injury: Monitor for elevations in transaminases and bilirubin.
  • Live and Oral Vaccines: Avoid use of live vaccines during vedolizumab treatment. Non-live vaccines may be administered, but response may be impaired.
  • Pregnancy: Limited data available. Use during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Pediatric Use

As of 2021, vedolizumab is approved for use in pediatric patients aged 5 years and older with moderately to severely active ulcerative colitis. Key points for pediatric use include:

  • Approval based on extrapolation of efficacy from adult UC studies and additional pharmacokinetic data in pediatric patients
  • Dosing is weight-based:
    • ≥ 40 kg: Adult dosing
    • 30 kg to < 40 kg: 220 mg
    • 20 kg to < 30 kg: 150 mg
    • 10 kg to < 20 kg: 80 mg
  • Safety profile in pediatric patients similar to that observed in adults
  • Ongoing studies are evaluating its use in pediatric Crohn's disease

Drug Interactions

Due to its gut-selective mechanism of action, vedolizumab has a low potential for drug interactions. However, some considerations include:

  • Natalizumab: Concurrent use is not recommended due to increased risk of progressive multifocal leukoencephalopathy (PML)
  • TNF Blockers: Concurrent use is not recommended due to potential increased risk of infections
  • Live Vaccines: Should be avoided during treatment with vedolizumab
  • Other Immunosuppressants: Use caution when administering vedolizumab with other immunosuppressive medications, as this may further increase the risk of infections

No formal drug interaction studies have been conducted with vedolizumab. Its lack of impact on systemic immunity suggests a low likelihood of affecting the pharmacokinetics of concomitant medications.



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