Infliximab and Vedolizumab

Mechanism

🧬 Infliximab

• Type: Chimeric IgG1 monoclonal antibody (mouse-human).
• Target: Potent inhibitor of tumor necrosis factor alpha (TNF-α).
• Extensive systemic immunosuppression, effective in systemic disorders and complex fistulas.

🩸 Vedolizumab

• Type: High selectivity humanized IgG1 monoclonal antibody.
• Target: Selective antagonist of heterodimeric integrin α₄β₇.
• Localized and selective immunosuppression restricted to the gastrointestinal tract.

Mechanism of action

Infliximab: Binds with high affinity to both the soluble and transmembrane forms of tumor necrosis factor alpha (TNF-α), a central proinflammatory cytokine of Th1 cellular immunity. By selectively occupying TNF-α, it prevents its binding and the subsequent signaling of TNF type I and II receptors located in the cells of the inflamed mucosa.

This action immediately neutralizes the inflamed inflammatory cascade, inhibits the synthesis of tissue-destructive metalloproteinases and, in addition, selectively induces cell lysis by antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of active TNF-secreting mononuclear immune cells.

Vedolizumab: It acts through a highly targeted and localized mechanism of action. It specifically binds to the α₄β₇integrin exposed on the surface of the gut-homing subpopulation of memory T helper lymphocytes.

Selective Exclusion Mechanism of Vedolizumab

Inflammatory T lymphocytes express the integrin α₄β₇, which interacts biologically with the mucosal targeting cell adhesion molecule type 1 (MAdCAM-1), selectively expressed in the capillary endothelium of the venules of the lamina propria of the intestinal mucosa and of the inflamed mesenteric lymph nodes. By blocking α₄β₇integrin, vedolizumab specifically prevents the physical adhesion and subsequent extravasation and migration of pathogenic T lymphocytes from the general circulation to the gastric or intestinal mucosa tissue.

Since MAdCAM-1 is not expressed in a relevant way in other organs of the body (such as the central nervous system or lung tissue), the immunosuppression induced by vedolizumab is strictly of a gastrointestinal regional nature, preserving peripheral systemic immune surveillance intact.

Pharmacokinetics

Pharmacokinetics

• Routes of Administration: Infliximab is exclusively administered slowly intravenously (currently there are subcutaneous maintenance presentations). Vedolizumab can be started intravenously and optionally continued by subcutaneous injection.
• Clearance and Half-Life: They are monoclonal antibodies that undergo non-specific proteolytic catabolism mediated by the reticuloendothelial system, without classical hepatic or renal clearance. The half-life of infliximab is approximately 8 to 10 days; that of vedolizumab is 25 days.

Indicators and dose

Approved indications

• Infliximab: Induction and maintenance of remission in moderate to severe active Crohn's disease (including complex active enterocutaneous fistulas) and in moderate to severe ulcerative colitis in adults and children over 6 years of age with refractory response to previous supportive treatments.
• Vedolizumab: Induction and maintenance of remission in ulcerative colitis and moderately to severely active Crohn's disease in adults with failure to immunomodulators or TNF-α antagonists.

Dosage and Clinical Adjustment

Infliximab (Standard induction and maintenance regimen):

• Induction: 5 mg/kg slowly intravenously (infusion over 2 hours) administered in weeks 0, 2 and 6 systematically.
• Maintenance: 5 mg/kg intravenously every 8 weeks continuously for life. In cases of secondary loss of response, the dose can be increased to 10 mg/kg or the interval shortened to every 4 or 6 weeks after monitoring trough serum levels.

Vedolizumab (Adults):

• Induction: 300 mg intravenously as a rapid 30-minute infusion in weeks 0, 2 and 6.
• Maintenance: 300 mg intravenously every 8 weeks. Alternatively, after induction, it can be administered by subcutaneous injection of 108 mg every 2 weeks continuously.

Clinical Adjustments: No dose adjustment is required in patients with hepatic or renal insufficiency, since monoclonal antibodies are cleared by pinocytosis and nonspecific proteolytic hydrolysis.

Security

Contraindications

• Infliximab (Absolutes): Severe active infections (sepsis, pneumonia, undrained abscesses). Untreated active or latent tuberculosis (blockade of TNF-α disorganizes tuberculous granulomas and can cause fatal dissemination of the mycobacteria). Advanced functional class congestive heart failure (NYHA III/IV), due to an increase in mortality associated with anti-TNF therapy.
• Vedolizumab (Absolutas): Severe uncontrolled active infections (pulmonary sepsis, meningitis).

Adverse effects (ADRs)

Drug interactions

• Vaccines with Live Attenuated Pathogens: The administration of live attenuated vaccines (such as yellow fever, measles, chickenpox or BCG) is strictly prohibited during active therapy with infliximab or vedolizumab and until at least 6 months after the last dose administered. Danger of vaccine-induced serious generalized disseminated infection.
• Association with Synthetic Immunosuppressants (Azathioprine): Concomitant use significantly reduces the immunogenicity and clearance rate of biological antibodies, increasing serum levels of the drug and reducing secondary failure due to the production of neutralizing antibodies of biological origin.

Safety of Use in Pregnant Women

Infliximab and Vedolizumab: Both actively cross the placental barrier from the second trimester of gestation in a manner facilitated by neonatal Fc receptors (FcRn). The available clinical data do not clearly indicate teratogenesis or specific toxicity. It is preferred to maintain active therapy during pregnancy to avoid severe relapses of maternal IBD. However, for infliximab, it is advisable to schedule the last infusion at week 32-34 to avoid high levels of the drug in the newborn, and the administration of the BCG vaccine is prohibited in the first 6-12 months of life of the exposed infant.