se activity in the cotton-top tamarin colitis model, and decrease synovitis andjoint erosions in a murine model of collagen-induced arthritis.
Infliximab products preventdisease in transgenic mice that develop polyarthritis as a result of constitutive expression ofhuman TNFα, and when administered after disease onset, allow eroded joints to heal.
12.2 Pharmacodynamics
Elevated concentrations of TNFα have been found in involved tissues and fluids of patientswith rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriaticarthritis and plaque psoriasis. In rheumatoid arthritis, treatment with infliximab productsreduced infiltration of inflammatory cells into inflamed areas of the joint as well asexpression of molecules mediating cellular adhesion [E-selectin, intercellular adhesionmolecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)], chemoattraction[IL-8 and monocyte chemotactic protein (MCP-1)] and tissue degradation [matrixmetalloproteinase (MMP) 1 and 3]. In Crohn’s disease, treatment with infliximab productsreduced infiltration of inflammatory cells and TNFα production in inflamed areas of theintestine, and reduced the proportion of mononuclear cells from the lamina propria able toexpress TNFα and interferon. After treatment with infliximab products, patients withrheumatoid arthritis or Crohn’s disease exhibited decreased levels of serum IL-6 and Creactiveprotein (CRP) compared to baseline. Peripheral blood lymphocytes from infliximab
product-treated patients showed no significant decrease in number or in proliferativeresponses to in vitro mitogenic stimulation when compared to cells from untreated patients.
In psoriatic arthritis, treatment with infliximab products resulted in a reduction in the numberof T-cells and blood vessels in the synovium and psoriatic skin lesions as well as a reduction.
The volume of distribution at steady state was independent of dose and indicated thatinfliximab was distributed primarily within the vascular compartment. Pharmacokineticresults for single doses of 3 mg/kg to 10 mg/kg in rheumatoid arthritis, 5 mg/kg in Crohn’sdisease, and 3 mg/kg to 5 mg/kg in plaque psoriasis indicate that the median terminal half-lifeof infliximab is 7.7 to 9.5 days.
Following an initial dose of infliximab, repeated infusions at 2 and 6 weeks resulted inpredictable concentration-time profiles following each treatment. No systemic accumulationof infliximab occurred upon continued repeated treatment with 3 mg/kg or 10 mg/kg at 4-or8week intervals. Development of antibodies to infliximab increased infliximab clearance. At8 weeks after a maintenance dose of 3 to 10 mg/kg of infliximab, median infliximab serum
concentrations ranged from approximately 0.5 to 6 mcg/mL; however, infliximabconcentrations were not detectable (<0.1 mcg/mL) in patients who became positive for
antibodies to infliximab. No major differences in clearance or volume of distribution wereobserved in patient subgroups defined by age, weight, or gender. It is not known if there aredifferences in clearance or volume of distribution in patients with marked impairment ofhepatic or renal function.
Infliximab pharmacokinetic characteristics (including peak and trough concentrations andterminal half-life) were similar in pediatric (aged 6 to 17 years) and adult patients withCrohn’s disease follow |
