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. 2009 Oct;68(4):561-73.
doi: 10.1111/j.1365-2125.2009.03494.x.

Development of a drug-disease simulation model for rituximab in follicular non-Hodgkin's lymphoma

David Ternant  1 , Emilie Hénin, Guillaume Cartron, Michel Tod, Gilles Paintaud, Pascal Girard
Affiliations

Development of a drug-disease simulation model for rituximab in follicular non-Hodgkin's lymphoma

David Ternant et al. Br J Clin Pharmacol. 2009 Oct.

Abstract

Aim: Rituximab has dramatically improved the survival of patients with non-Hodgkin's lymphomas (NHL), but the dosing regimen currently used should be optimized. However, the concentration-effect relationship of rituximab has never been described by pharmacokinetic-pharmacodynamic (PK-PD) modelling, precluding the simulation of new dosing regimens. The aim of this study was to develop a PK-PD model of rituximab in relapsed/resistant follicular NHL (FL).

Methods: A model describing the relationship between rituximab concentrations and progression-free survival (PFS) was developed using data extracted from the pivotal study, which evaluated 151 relapsed/resistant FL patients. The influence of FCGR3A genetic polymorphism on the efficacy of rituximab was quantified using data from 87 relapsed/resistant FL patients. The predictive performance of the model was analysed using two independent datasets: a study that evaluated rituximab combined with chemotherapy [rituximab, cyclophosphamide, vincristine, adriamycin and prednisone (R-CHOP)] in 334 relapsed/resistant FL patients and a study that evaluated rituximab monotherapy in 47 asymptomatic FL patients with known FCGR3A genotype.

Results: For R-CHOP, observed and model-predicted PFS (90% confidence interval) at 24 months were 0.50 and 0.48 (0.40, 0.56), respectively, for the observation arm, and 0.62 and 0.59 (0.50, 0.65), respectively, for the rituximab maintenance arm. For rituximab monotherapy, observed and predicted PFS at 24 months were 0.67 and 0.63, respectively, for FCGR3A-V/V patients, and 0.41 and 0.36 (0.25, 0.49), respectively, for FCGR3A-F carriers.

Conclusions: Our model provides a satisfactory prediction of PFS at 24 months. It can be used to simulate new dosing regimens of rituximab in populations of FL patients and should improve the design of future clinical trials.

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Figures

Figure 1
Figure 1
Flow chart of the study. The study consists of three steps: obtaining data, model building and validation steps. Abbreviations are explained within in the text
Figure 2
Figure 2
Results of model building for median rituximab concentrations (A) and progression-free survival (PFS) (B). For all patients, observations are displayed as closed and open circles for all patients and responders, respectively. Predictions are displayed as solid and dashed lines for all patients and responders, respectively. (C) Reduction of λmaxvs. mean-time concentration. VV and Fx patients are displayed as solid and dashed lines, respectively
Figure 3
Figure 3
Visual predictive checks of studies A, B, C and D. Visual predictive checks of study A (A), study B (B), study C which compared rituximab, cyclophosphamide, vincristine, adriamycin and prednisone (R-CHOP) without maintenance (C1) and R-CHOP with maintenance (C2), and study D (D). The solid lines are observed progression-free survival (PFS) and the dashed lines are 5th, 50th and 95th percentiles of predicted PFS. The 5th and 95th percentiles determine the 90% confidence interval (CI). In study B and D, the PFS of Fx and VV patients are displayed as black and grey lines, respectively. The value of PFS at 24 months (vertical dashed lines) is given in Table 3. In Figure 3D, the confidence interval for VV patients is too large to be represented
Figure 4
Figure 4
Sensitivity analysis for fixed parameters. Sensitivity analysis of fixed parameters ωCm50 (%), λmax (month−1) and γVV in study A (A) and B (B). The meaning of these parameters is described in the text. This analysis was made with data of study A for ωCm50 and λmax and with data of study A and B for γVV. For each parameter, 500 simulations were made for each value of parameters. The 5th, 50th and 95th percentiles of progression-free survival (PFS) predictions are displayed at 20 months for study A and at 24 months for study B. The observed value at this time is displayed as dashed lines
Figure 5
Figure 5
Simulated progression-free survival (PFS) up to 24 months for different dosing regimens and in two FCGR3A genotypes. Three dosing regimens were simulated in asymptomatic follicular lymphoma (FL) treated by rituximab alone: (1) 4 weekly 375 mg m−2 doses, (2) 4 weekly 750 mg m−2 doses and (3) 4 weekly 375 mg m−2 doses followed by a maintenance of 375 mg m−2 every 2 months, in FcγRIIIa-158 VV (a) and F carrier patients (b)
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