Adalimumab

Abstract

Adalimumab (Humira®) is a recombinant, fully human IgG1 monoclonal antibody that binds specifically to tumor necrosis factor (TNF)-α, thereby neutralizing the activity of the cytokine. Subcutaneous adalimumab has been investigated in well designed trials in patients with active rheumatoid arthritis despite treatment with disease-modifying antirheumatic drugs (DMARDs). Patients receiving adalimumab 40mg every other week in combination with methotrexate (Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab [ARMADA] and DE019 trials) or standard antirheumatic therapy (Safety Trial of Adalimumab in Rheumatoid Arthritis [STAR] trial) for 24–52 weeks had significantly higher American College of Rheumatology (ACR) 20, ACR50, and ACR70 response rates than patients receiving placebo plus methotrexate or standard antirheumatic therapy. In ARMADA, an ACR20 response was achieved in 25%, 52%, and 67% of adalimumab plus methotrexate recipients at weeks 1, 4, and 24, respectively. In ARMADA and DE019, improvements in the individual components of the ACR response were significantly greater with adalimumab 40mg every other week plus methotrexate than with placebo plus methotrexate. Monotherapy with adalimumab 40mg every other week was associated with significantly higher ACR20, ACR50, and ACR70 response rates than placebo, as well as significantly greater improvements in the individual components of the ACR response. ACR responses were sustained with adalimumab according to the results of extension studies in which patients received adalimumab in combination with methotrexate (up to 30 months) or as monotherapy (up to 5 years). In both concomitant therapy and monotherapy trials, adalimumab was associated with significantly greater improvements from baseline in health-related quality of life (HR-QOL) measures than placebo; adalimumab also retarded the radiographic progression of structural joint damage to a significant extent compared with placebo. Adalimumab was generally well tolerated as both concomitant therapy and monotherapy. In ARMADA, there were no significant differences between adalimumab and placebo (in combination with methotrexate) in the incidence of adverse events; however, in STAR, the incidence of injection site reactions, rash, and back pain was significantly higher with adalimumab than with placebo (in combination with standard antirheumatic therapy). No cases of tuberculosis were reported in either trial. In conclusion, subcutaneous adalimumab in combination with methotrexate or standard antirheumatic therapy, or as monotherapy, is effective in the treatment of adults with active rheumatoid arthritis who have had an inadequate response to DMARDs. Adalimumab has a rapid onset of action and sustained efficacy. The drug also retards the progression of structural joint damage, improves HR-QOL, and is generally well tolerated. Thus, adalimumab is a valuable new option for the treatment of DMARD-refractory adult rheumatoid arthritis. Adalimumab is a recombinant, fully human IgG1 monoclonal antibody composed of heavy and light chain variable regions and IgG1 : κ constant regions. It binds specifically to tumor necrosis factor (TNF)-α, thereby preventing the binding of TNFα to p55 and p75 receptors and neutralizing the activity of the cytokine. In vitro, an adalimumab concentration of 0.16 nmol/L was required to inhibit binding of TNFα to its receptor on human U937 cells by 50%. Adalimumab demonstrated TNFα neutralizing capabilities in several in vitro models and in a murine model. In patients with active rheumatoid arthritis, adalimumab, but not placebo, significantly increased total TNFα levels (free and bound in TNF/adalimumab complexes) from baseline. Systemic levels of TNFα mRNA did not change, although p75 and p55 soluble TNF receptor levels and systemic levels of interleukin (IL)-1β mRNA, IL-1 receptor antagonist, and IL-6 decreased from baseline to a significant extent with adalimumab. No consistent immunohistologic changes were observed 2 weeks after drug administration in patients with rheumatoid arthritis who received adalimumab and underwent synovial biopsies. Significant reductions from baseline in levels of matrix metalloproteinases occurred with adalimumab. In addition, levels of other markers of cartilage and synovium turnover (e.g. cartilage oligomeric matrix protein, intercellular adhesion molecule-1, and human cartilage glycoprotein-39) were significantly reduced with adalimumab. Adalimumab did not adversely affect immune function in patients with rheumatoid arthritis, although a slight increase in peripheral lymphocyte percentages occurred in adalimumab recipients compared with placebo recipients. Polymorphonuclear cell function was not impaired by adalimumab. A maximum serum adalimumab concentration (C_max) of 4.7 μg/mL was reached 131 hours (t_max) after a single subcutaneous 40mg dose in healthy adults (average absolute bioavailability of 64%). At steady state, the mean trough serum adalimumab concentration was 5.83 and 3.80 μg/mL when subcutaneous adalimumab 40mg every other week was administered with and without methotrexate in patients with rheumatoid arthritis. Mean C_max values were 9.97 and 7.70 μg/mL with and without methotrexate, with corresponding mean t_max values of 83.2 and 89.6 hours. During the dosing interval, mean area under the serum concentration-time curve values for adalimumab were 2563 and 1832 μg · h/mL when the drug was administered with and without methotrexate. Minimal fluctuation of steady-state adalimumab concentrations was observed during a dosing interval; average steady-state serum concentrations of the drug were 7.63 and 5.45 μg/ mL with and without methotrexate. The mean volume of distribution following intravenous administration of adalimumab 0.5–10 mg/kg was estimated to be...