Infliximab Treatment Does Not Lead to Full TNF-alpha Inhibition: A Target-Mediated Drug Disposition Model

Background and Objective Infliximab, an anti-tumour necrosis factor (TNF)-alpha monoclonal antibody, has been approved in chronic inflammatory disease, including rheumatoid arthritis, Crohn's disease and ankylosing spondylitis. This study aimed to investigate and characterise target-mediated drug disposition of infliximab and antigen mass turnover during infliximab treatment. Methods In this retrospective cohort of 186 patients treated with infliximab for rheumatoid arthritis, Crohn's disease or ankylosing spondylitis, trough infliximab concentrations were determined from samples collected between weeks 0 and 22 after treatment initiation. Target-mediated pharmacokinetics of infliximab was described using target-mediated drug disposition modelling. Target-mediated elimination parameters were determined for rheumatoid arthritis and Crohn's disease, assuming ankylosing spondylitis with no target-mediated elimination. Results The quasi-equilibrium approximation of a target-mediated drug disposition model allowed a satisfactory description of infliximab concentration-time data. Estimated baseline TNF-alpha amounts were similar in Crohn's disease and rheumatoid arthritis (R0 = 0.39 vs 0.46 nM, respectively), but infliximab-TNF complex elimination was slower in Crohn's disease than in rheumatoid arthritis (k(int) = 0.024 vs 0.061 day(-1), respectively). Terminal elimination half-lives were 13.5, 21.5 and 16.5 days for rheumatoid arthritis, Crohn's disease and ankylosing spondylitis, respectively. Estimated amounts of free target were close to baseline values before the next infusion suggesting that TNF-alpha inhibition may not be sustained over the entire dose interval. Conclusions The present study is the first to quantify the influence of target antigen dynamics on infliximab pharmacokinetics. Target-mediated elimination of infliximab may be complex, involving a multi-scale turnover of TNF-alpha, especially in patients with Crohn's disease. Additional clinical studies are warranted to further evaluate and fine-tune dosing approaches to ensure sustained TNF-alpha inhibition.