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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The concentration-effect relationship of rituximab in follicular lymphoma (FL) was previously described using pharmacokinetic-pharmacodynamic (PK-PD) modelling.• The influence of genetic polymorphism of FCGR3A on rituximab efficacy in FL patients was included in this PK-PD model.• Previous studies suggest that increasing the dose of rituximab and/or the number of infusions may lead to a better clinical response in FL. WHAT THIS STUDY ADDS• The previously validated PK-PD model can be used to design an optimized rituximab dose regimen in FL patients.• Clinical trial simulation shows the potential clinical benefits of changes in rituximab dose.• Optimization of the rituximab dose regimen cannot compensate for the lower response of FCGR3A-158F carriers compared with that of FCGR3A-158VV patients. AIMSRituximab 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. 375 mg m -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. METHODSA 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 FcgRIIIa 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%. RESULTSThe model predicted a potential benefit of 1500 mg m -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. CONCLUSIONOur 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.

Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study Association report

“…7,13,35 Higher frequency of 375 mg/m 2 rituximab infusions did not result in better outcomes in all patients as compared with the classical regimen. 4,36 The SEXIE-R-CHOP-14 study demonstrated that an increased rituximab dose of 500 mg/m 2 in elderly male patients resulted in improved outcome.…”

Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

“…Furthermore, the fact that NK cells from F/F donors require higher concentrations of RTX for ADCC in vitro compared with V/V carriers 87 suggests that increasing RTX doses in vivo may overcome the effect of FcγRIIIA polymorphisms. 94 An effect of FcγRIIIA polymorphism has, however, not been observed in CLL 95 or in FL patients treated with RTX and chemotherapy, probably due to dilution of the effect by standard drugs. 96 In large studies of DLBCL treated with R-CHOP, there are reports of a trend for better response of V/V and V/F patients compared with F/F.…”

The evaluation and optimal use of rituximab in lymphoid malignancies

“…Few studies have investigated the pharmacokinetics of rituximab when administered with other drugs or at different intervals. 42,43 The PK profile of rituximab when administered as part of an R-CHOP chemotherapy was recently reported by Blasco et al 44 They found that PK parameters were similar to those described for studies in the absence of chemotherapy. In addition, the authors did not observe any intra-subject variation in pharmacokinetic parameters over the treatment period.…”