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Infliximab - Arthritides - Monoclonal Antibodies in Anti inflammatory Therapy

Infliximab neutralizes biological activity of both soluble and transmembrane forms of TNF-a, but does not neutralize TNF-b (also known as lymphotoxin-a ), which utilizes the same receptors as TNF-a. Infliximab is the only anti-TNF agent given intrave-nously, but has the longest potential dosing interval.

Infliximab

 

Infliximab neutralizes biological activity of both soluble and transmembrane forms of TNF-a, but does not neutralize TNF-b (also known as lymphotoxin-a ), which utilizes the same receptors as TNF-a. Infliximab is the only anti-TNF agent given intrave-nously, but has the longest potential dosing interval. It was also the first Food and Drug Administration (FDA) approved anti-TNF agent and has approvals in RA, PsA, AS, UC, adult and pediatric CD, and PP. For RA it is approved in combination with methotrexate “for reducing signs and symptoms, inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active” disease. Pharmacokinetic studies in adults with single intravenous infusions of infliximab at 3 to 10 mg/kg showed linear kinetics, a median terminal half-life of 8.0 to 9.5 days, and the volume of distribution at steady state was independent of dose (i.e., primarily distributed within the vascular com-partment). Multiple dose studies of IV infusions of infliximab at 3 to 10 mg/kg every 4 to 8 weeks showed no systemic accumulation, and after 8 weeks of maintenance dosing the median infliximab concentra-tions ranged from 0.5 to 6 mg/mL. Patients who developed anti-drug antibodies had increased drug clearance and undetectable (< 0.1 mg/mL) serum trough concentrations at 8-week dosing intervals. No major differences in clearance or volume of distribu-tion were observed in patient subsets defined by age, weight or gender, but it is unknown if these parameters are affected by impairment of renal or hepatic function.

 

 

 

The recommended dose of infliximab for RA is 3 mg/kg IV infusion given on an induction schedule at 0, 2, and 6 weeks followed by infusions every8 weeks, though patients with incomplete responses may be given up to 10 mg/kg IV every 4 weeks. As a chimeric antibody infliximab is expected to have a higher rate of immunogenicity, and though the package insert mentions a rate of formation of anti-drug antibodies of approximately 10%. Higher rates are quoted in the literature and patients with anti-drug antibodies are more likely to have higher rates of drug clearance, reduced efficacy and a 2- to 3-fold increased incidence of infusion reactions. Other safety issues with infliximab include an increased risk of serious and opportunistic infections, malignancy, heart failure, and a significantly increased incidence of seroconversion for anti-nuclear (ANA) antibodies and anti-dsDNA antibodies. The label includes a black box warning and more specifics on infection and malignancy risks, and there is a contraindication for use of > 5 mg/kg dosing in patients with moderate to severe heart failure (St. Clair et al., 2002; package insert for Remicade, 2006).


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