Model-based design of rituximab dosage optimization in follicular non-Hodgkin's lymphoma

Abstract

AIMS Rituximab has dramatically improved the survival of patients with non-Hodgkin's lymphoma (NHL). However, studies have suggested that the dose regimen currently used (i.e. 375mgm -2) could be optimized. The aims of this study were to quantify the benefits of the new dose regimen for rituximab in follicular NHL (FL) patients using a previously validated PK-PD model and to design clinical trials investigating optimization of rituximab dosage. METHODS A PK-PD model was used to predict progression-free survival (PFS) of FL patients treated by rituximab alone in asymptomatic FL, and those treated by rituximab combined with chemotherapy (R-CHOP) in relapsed/resistant FL. This model accounts for the influence of a polymorphism in FCGR3A, the gene encoding the FcγRIIIa receptor, on clinical efficacy. Several induction and maintenance dose regimens using rituximab alone or in combination with conventional chemotherapy (CHOP) were tested. The benefits of rituximab dose adjustment for F carriers were investigated. The numbers of subjects required for the design of two-armed clinical trials were calculated using model-predicted PFS at a power of 80%. RESULTS The model predicted a potential benefit of 1500mgm -2 maintenance doses of rituximab for both rituximab monotherapy and R-CHOP. The model shows that the PFS of FCGR3A-F carriers remains lower than that of homozygous FCGR3A-VV patients, even with markedly increased rituximab doses. CONCLUSION Our results suggest a benefit of increasing doses of rituximab in FL, both during induction and maintenance. These results need to be confirmed in controlled clinical trials. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.