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

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.

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.

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.

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.