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

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 (k 10 ) increased with CD19+ count ( P = 0.00022) and IgG concentration ( P = 7.4 × 10 −8 ), and that k 10 decreased with time ( P = 0.00015), partly explained by a change in target‐antigen amount. Conclusions The association between CD19+ count and k 10 may be explained by target‐mediated drug disposition, while the association between IgG serum concentration and k 10 may be explained by a saturation of the neonatal Fc receptor at high IgG concentrations, resulting in decreased recycling of rituximab.