Model-based design of rituximab dosage optimization in follicular non-Hodgkin's lymphoma |
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Authors: | Ternant David Cartron Guillaume Hénin Emilie Tod Michel Girard Pascal Paintaud Gilles |
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Affiliation: | Université Fran?ois Rabelais de Tours, Laboratoire de Pharmacologie-Toxicologie, CHRU Tours, 2 boulevard Tonnellé, Tours Cedex, France. david.ternant@free.fr |
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Abstract: | 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 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%.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. |
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Keywords: | follicular lymphoma PK–PD modelling progression-free survival rituximab trial simulation |
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