Remicade

[Infliximab]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

General

Infliximab neutralizes the biological activity of TNFa by binding with high affinity to the soluble and transmembrane forms of TNFa and inhibits binding of TNFa with its receptors. Infliximab does not neutralize TNFß (lymphotoxin a), a related cytokine that utilizes the same receptors as TNFa. Biological activities attributed to TNFa include: induction of pro-inflammatory cytokines such as interleukins (IL) 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes.

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Cells expressing transmembrane TNFa bound by infliximab can be lysed in vitro3 or in vivo.4 Infliximab inhibits the functional activity of TNFa in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils, B and T lymphocytes, and epithelial cells. Anti-TNFa antibodies reduce disease activity in the cotton-top tamarin colitis model, and decrease synovitis and joint erosions in a murine model of collagen-induced arthritis. Infliximab prevents disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFa, and when administered after disease onset, allows eroded joints to heal.

Pharmacodynamics

Elevated concentrations of TNFa have been found in the joints of rheumatoid arthritis patients and the stools of Crohn’s disease patients and correlate with elevated disease activity. In rheumatoid arthritis, treatment with REMICADE reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion [E-selectin, intercellular adhesion molecule-1(ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)], chemoattraction [IL-8 and monocyte chemotactic protein (MCP-1)], and tissue degradation [matrix metalloproteinase (MMP) 1 and 3].

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