Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients

摘要

Aims Rituximab is a monoclonal antibody directed against CD20, which is approved in rheumatoid arthritis (RA). This study aimed at assessing the influence of CD19+ cell counts as target‐antigen amount, and of immunoglobulin G (IgG) serum concentrations on rituximab pharmacokinetics in RA patients. Methods In a cohort of 64 RA patients who had received repetitive courses of rituximab, the influence of CD19+ cell count, IgG serum concentration, body surface area, sex and disease activity score in 28 joints on rituximab pharmacokinetic parameters was assessed using a population pharmacokinetic analysis. Results A two‐compartment model, with first‐order distribution and elimination best described the data. The volume of distribution of central compartment and clearance of rituximab were estimated at 4.7?l and 0.56?l?day–1, respectively. Distribution and elimination half‐lives were 0.9?days and 17.3?days, respectively. As expected, the central volume of distribution increased with body surface area ( P =?0.012) and was higher in male than in female ( P =?0.004). We found that the elimination rate constant (k₁₀) increased with CD19+ count ( P =?0.00022) and IgG concentration ( P =?7.4 × 10?8), and that k₁₀ decreased with time ( P =?0.00015), partly explained by a change in target‐antigen amount. Conclusions The association between CD19+ count and k₁₀ may be explained by target‐mediated drug disposition, while the association between IgG serum concentration and k₁₀ may be explained by a saturation of the neonatal Fc receptor at high IgG concentrations, resulting in decreased recycling of rituximab.