A Pilot Dose-Finding Study of Etanercept in Rheumatoid Arthritis

A randomized, parallel-dose study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of etanercept in 61 patients with rheumatoid arthritis (RA) who received doses from 10 mg once-weekly to 50 mg twice-weekly for 4 weeks. Empiric application of a maximal-effect (E_max ) model to pooled steady-state concentrations (C_ss ) and PD markers provided half-maximal-effect concentration estimates of 567, 573, 465, 87, and 159 ng/mL for change from baseline in number of swollen joints, number of painful joints, erythrocyte sedimentation rate, interleukin-6, and matrix metalloproteinase-3, respectively. C_ss >∼2,000 ng/mL did not appear to offer additional benefit. It was concluded that the middle doses, 10 mg twice-weekly, 50 mg every 2 weeks, and 50 mg once-weekly, would provide C_ss in the target range of 500-2,000 ng/mL. The revised US Food and Drug Administration guideline for development of medicines for treatment of RA encourages a study design incorporating PK/PD assessment to inform later studies.