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.