Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis

Purpose Infliximab, a monoclonal antibody, is approved for the treatment of inflammatory diseases at doses that depend on the patient disease population. It was the aim of this study to evaluate its population pharmacokinetics in patients with moderately to severely active ulcerative colitis and characterize patient covariates that affect its disposition in this population. Methods Information collected from 482 patients in two randomized, double-blind, placebo-controlled international studies were analyzed using NONMEM. Results A two-compartment, population pharmacokinetic model described the serum infliximab concentration-time data. Population pharmacokinetic estimates (typical value ± standard error), based on the final covariate model, were clearance (CL: 0.407 ± 0.0103 L/day), apparent volumes of distribution in the central (V₁: 3.29 ± 0.0679 L) and peripheral (V₂: 4.13 ± 0.16 L) compartments, and intercompartment clearance (Q: 7.14 ± 0.489 L/day). Infliximab exhibited interindividual variability for CL and V₁ of 37.7% and 22.1%, respectively. Infliximab t₁/₂ is approximately 14 days. Covariate analysis showed that V₁ increased as body weight increased, and CL was higher in patients who developed antibodies to infliximab. An additional novel covariate, serum albumin concentration, was found to be inversely and strongly related to infliximab clearance in this population. Conclusions The disposition of infliximab in patients with moderately to severely active ulcerative colitis, unlike in rheumatoid arthritis, was not affected by coadministration of immunomodulators and corticosteroids but was related to formation of antibodies to infliximab and, notably, to serum albumin levels.