A Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Vedolizumab

Abstract

Vedolizumab is a humanized anti-α4β7 integrin monoclonal antibody that selectively blocks trafficking of memory T cells to inflamed gut tissue by inhibiting the α4β7-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. Approved for treating patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD), vedolizumab is administered as a 300 mg intravenous infusion. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations. At therapeutic concentrations, vedolizumab primarily undergoes linear elimination. From population pharmacokinetic modeling, the vedolizumab terminal elimination half-life (t ½ β) was estimated to be 25.5 days; linear clearance (CLL) was similar for patients with UC (0.159 L/day) and CD (0.155 L/day). Extreme low albumin concentrations and extreme high body weight values were potentially clinically important predictors of vedolizumab CLL. Other factors, including concomitant therapy use (methotrexate, azathioprine, mercaptopurine, or aminosalicylates) or prior tumor necrosis factor-α (TNF-α) antagonist use, had no clinically relevant effects on CLL. A positive exposure–efficacy relationship for clinical remission and clinical response was apparent for vedolizumab induction therapy in patients with UC or CD. On average, patients with higher albumin, lower fecal calprotectin (UC only), lower C-reactive protein (CD only), and no prior TNF-α antagonist use had a higher probability of remission. Off drug, 10% of patients with UC or CD were positive for anti-drug antibodies. This article provides a comprehensive review of the clinical pharmacokinetics, pharmacodynamics, exposure–efficacy relationships, and immunogenicity of vedolizumab.

Systematic review with meta‐analysis: association between vedolizumab trough concentration and clinical outcomes in patients with inflammatory bowel diseases

“…From these, 32 studies focusing on vedolizumab were identified for full text review, and five studies were included in quantitative synthesis (Figure ) . Additionally, data from five studies was qualitatively synthesized to inform vedolizumab concentrations associated with favourable outcomes . Multiple studies were reported using the GEMINI trials and unique aspects of each analyses were used to quantitatively or qualitatively inform evidence on role of TDM with vedolizumab.…”

“…It is unclear whether “subtherapeutic” vedolizumab concentration (below these thresholds) is a consequence of rapid drug clearance or the cause of inadequate response. Mechanistically, unlike cytokine antagonists, vedolizumab binds to the α 4 β 7 integrin and blocks lymphocyte interaction with mucosal addressin cell adhesion molecule‐1 expressed on the endothelium of mesenteric lymph nodes and gastrointestinal mucosa, impairing the migration of gut‐homing lymphocytes into gastrointestinal mucosa . Recent studies have suggested that vedolizumab may exert it's clinical effect through additional mechanisms of action.…”

Passive Monoclonal and Polyclonal Antibody Therapies

“…This medication is also FDA approved for UC. 270,271 Infliximab (Remicade, Inflectra, Remsira) is a chimeric Mab (IgG1k) with specificity to TNF-a and is FDA approved for IBD and multiple inflammatory arthritic diseases. This medication allows for steroid-free remission within months of starting therapy.…”

A review of vedolizumab and ustekinumab for the treatment of inflammatory bowel diseases

“…Overall immunogenicity for vedolizumab appears to be low in comparison with conventional anti‐TNF agents. When patients who received/had not received concomitant immunosuppressant at baseline were compared, the risk of developing anti‐vedolizumab antibody was only marginally lower, 3% versus 4% …”

“…As little as 2 mg/kg of vedolizumab is sufficient to saturate most α4β7 integrin receptors. Furthermore, receptor occupancy does not correlate with treatment response . It is unclear if this may be related to other unknown mechanisms of action that may benefit from a higher level of vedolizumab …”