title: Model-based design of rituximab dosage optimization in follicular non-Hodgkin's lymphoma.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
  
  
  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 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.
  
  
  CONCLUSIONS
  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.
authors: Université François Rabelais de Tours, Laboratoire de Pharmacologie-Toxicologie, CHRU Tours, 2 boulevard Tonnellé, Tours Cedex, France. david.ternant@free.fr
authors: David
authors: D
authors: Ternant
authors: Guillaume
authors: G
authors: Cartron
authors: Emilie
authors: E
authors: Hénin
authors: Michel
authors: M
authors: Tod
authors: Pascal
authors: P
authors: Girard
authors: Gilles
authors: G
authors: Paintaud
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000235:genetics; D008954:Models, Biological; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C496124:FCGR3A protein, human; D017452:Receptors, IgG; D000069283:Rituximab