Population pharmacokinetics of rituximab in patients with diffuse large B‐cell lymphoma and association with clinical outcome

AIMS Pharmacokinetic (PK) studies suggest that there is a room for improvement in clinical use of rituximab through more individualized treatment. The objective of this study was to characterize rituximab PK in 29 newly diagnosed patients with diffuse large B-cell lymphoma treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine and methylprednisolone every 3 weeks. We also evaluated the association of rituximab PK with clinical outcome. METHODS Rituximab serum levels were determined by enzyme-linked immunosorbent assay and evaluated by a population PK analysis applying nonlinear mixed effects modelling. RESULTS The data were best described by a two-compartment model comprising linear nonspecific clearance of 0.252 [95% confidence interval (CI): 0.227-0.279] l day-1 and time-varying specific clearance of 0.278 (95% CI: 0.181-0.390) l day-1 , corresponding to target-mediated drug disposition of rituximab. Nonspecific clearance was lower in older patients and those with lower body weight. Additionally, volume of the central compartment was higher in males. A clear association of clinical response with rituximab PK has been observed. Rate constant of specific clearance decay was 0.143 day-1 (95% CI: 0.0478-0.418) in patients with no disease progression, while in patients with disease progression it was 82.2% lower (95% CI: 33.4-95.0). CONCLUSIONS This finding indicates that time-changes in clearance could serve as a predictive marker of response to rituximab. Our report demonstrates the rationale for studies evaluating higher doses of rituximab in selected patients.