Relationship Between Metabolic Tumor Volume and Rituximab Pharmacokinetic Parameters in Non-Hodgkin’s Lymphoma

The pharmacokinetics (PK) of the monoclonal antibody rituximab in B-cell lymphomas presents a high interindividual variability. In the pivotal study, inverse correlation between rituximab concentration and tumor burden estimated by the measurement of tumor bulk at baseline has been observed (Berinstein and al., Ann. Oncol. 1998). Using a pharmacokinetic/pharmacodynamic (PK/PD) model, it has been demonstrated in a murine model of lymphoma-expressing CD20 that tumor burden influences rituximab concentration (Dayde and al., Blood 2009). The aim of the present study was to evaluate the relationship between rituximab pharmacokinetic (PK) parameters and metabolic tumor volume (MTV) in patients with a previously untreated CD20-positive non-Hodgkin's lymphoma.

Twenty-five patients (12 follicular and 13 diffuse large B-cell lymphoma) received a combination of rituximab (dose of 375 mg/m²) with 6 to 8 cycles of CHOP. All patients provided written informed consent for the study. Rituximab serum levels were measured using a validated enzyme-linked immunosorbent assay (ELISA). Tumor volume delineations were performed on ¹⁸F-FDG PET-scan at baseline (Planet Onco, Dosisoft, France). Rituximab PK was assessed using population compartmental modelling. A relationship between MTV and survival was described.

Estimations of typical (interindividual standard deviation) systemic clearance (CLc) and volume of distribution (Vc) were 0.00972 L.h^-1 and 3.12 L, respectively. Median MTV was 600 mL (range, 7 - 6217 mL). The central volume of distribution and the systemic clearance increased with MTV (p<0.05) (Table). A high MTV (>600 mL) was significantly associated with decreased event-free survival (p<0.05).

This pilot study is the first to describe a correlation between initial imaging-calculated metabolic tumor volume as a continuous variable and rituximab PK parameters in patients treated with R-chemotherapy for B-cell lymphomas. An increase in MTV leaded to a decrease in exposure to rituximab. Further prospective investigations on rituximab PK and dose adjustments in relationship with tumor burden are needed. Increased rituximab dose should be considered in patients with high tumor burden.