A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis.

OBJECTIVE: To assess the pharmacokinetics, safety profile, and efficacy of the fully human anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibody adalimumab (D2E7) in patients with long-standing, active rheumatoid arthritis (RA). METHODS: This was a randomized, double blind, placebo controlled study of single intravenous injections of ascending doses (0.5 to 10 mg/kg) of adalimumab in 5 cohorts of 24 patients each (18 adalimumab and 6 placebo in all cohorts except the 0.5 mg/kg cohort of 17 adalimumab, 7 placebo). A total of 120 patients participated (adalimumab 89, placebo 31). The clinical response was measured by changes in composite scores defined by the criteria of the European League Against Rheumatism (EULAR) and the American College of Rheumatology. RESULTS: Single doses of adalimumab showed a rapid onset of clinical effect (24 hours to 1 week), with peak efficacy at 1 to 2 weeks that was sustained for at least 4 weeks and for as long as 3 months in some patients. EULAR response was seen at least once during the 4 week period after drug injection in 29% of patients in the placebo group as well as in 41%, 78%, 72%, 89%, and 100% in the 0.5, 1, 3, 5, and 10 mg/kg groups, respectively. No dose related increases in adverse events were observed in the adalimumab patients compared with the placebo group. Adalimumab systemic drug exposure (AUC0-( )) increased linearly with an increase in dose. The mean total serum clearance was 0.012 to 0.017 l/h, and the steady-state volume of distribution ranged from 4.7 to 5.5 l. The estimated mean terminal half-life ranged from 10.0 to 13.6 days for the 5 cohorts, with an overall mean half-life of 12 days. CONCLUSION: Treatment with the fully human Mab adalimumab was safe and well tolerated when administered as a single intravenous injection at doses up to 10 mg/kg, and was associated with a clinically significant improvement in the signs and symptoms of active RA