Model‐based design of rituximab dosage optimization in follicular non‐Hodgkin's lymphoma
- 12 March 2012
- journal article
- Published by Wiley in British Journal of Clinical Pharmacology
- Vol. 73 (4), 597-605
- https://doi.org/10.1111/j.1365-2125.2011.04125.x
Abstract
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. 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. 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. 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. 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%. The 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. 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.Keywords
This publication has 35 references indexed in Scilit:
- Mechanism-Based Approach to the Economic Evaluation of PharmaceuticalsPharmacoEconomics, 2012
- Rituximab Maintenance Treatment of Relapsed/Resistant Follicular Non-Hodgkin's Lymphoma: Long-Term Outcome of the EORTC 20981 Phase III Randomized Intergroup StudyJournal of Clinical Oncology, 2010
- Development of a drug–disease simulation model for rituximab in follicular non‐Hodgkin's lymphomaBritish Journal of Clinical Pharmacology, 2009
- Maintenance Rituximab After Cyclophosphamide, Vincristine, and Prednisone Prolongs Progression-Free Survival in Advanced Indolent Lymphoma: Results of the Randomized Phase III ECOG1496 StudyJournal of Clinical Oncology, 2009
- Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 studyBlood, 2008
- Rituximab Added to First-Line Mitoxantrone, Chlorambucil, and Prednisolone Chemotherapy Followed by Interferon Maintenance Prolongs Survival in Patients With Advanced Follicular Lymphoma: An East German Study Group Hematology and Oncology StudyJournal of Clinical Oncology, 2007
- Pharmacokinetics of rituximab and its clinical use: Thought for the best use?Critical Reviews in Oncology/Hematology, 2007
- Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study GroupBlood, 2005
- Long-Term Results of the R-CHOP Study in the Treatment of Elderly Patients With Diffuse Large B-Cell Lymphoma: A Study by the Groupe d'Etude des Lymphomes de l'AdulteJournal of Clinical Oncology, 2005
- Maximizing Therapeutic Benefit of Rituximab: Maintenance Therapy Versus Re-Treatment at Progression in Patients With Indolent Non-Hodgkin's Lymphoma—A Randomized Phase II Trial of the Minnie Pearl Cancer Research NetworkJournal of Clinical Oncology, 2005