Population Pharmacodynamic Modelling of the CD19+ Suppression Effects of Rituximab in Paediatric Patients with Neurological and Autoimmune Diseases

Abstract

Background: Limited pharmacotherapy and the failure of conventional treatments in complex pathologies in children lead to increased off-label use of rituximab. We aimed to characterize the time course of CD19+ B lymphocytes (CD19+) under treatment with intravenous rituximab in children with neurologic and autoimmune diseases and to evaluate the impact of covariates (i.e., demographics, diagnosis and substitution between innovator and biosimilar product) on rituximab pharmacodynamics and disease activity.

Methods: Pre- and post-drug infusion CD19+ in peripheral blood were prospectively registered. A population pharmacodynamic model describing the time course of CD19+ was developed with NONMEM v7.4. Simulations of three different rituximab regimens were performed to assess the impact on CD19+. Logistic regression analysis was performed to identify predictors of clinical response recorded through disease activity scores.

Results: 281 measurements of CD19+ lymphocyte counts obtained from 63 children with neurologic (n = 36) and autoimmune (n = 27) diseases were available. The time course of CD19+ was described with a turn-over model in which the balance between synthesis and degradation rates is disrupted by rituximab, increasing the latter process. The model predicts half-lives (percent coefficient of variation, CV(%)) of rituximab and CD19+ of 11.6 days (17%) and 173.3 days (22%), respectively. No statistically significant effect was found between any of the studied covariates and model parameters (p > 0.05). Simulations of different regimens showed no clinically significant differences in terms of CD19+ repopulation times. A trend towards a lack of clinical response was observed in patients with lower CD19+ repopulation times and higher areas under the CD19+ versus time curve.

Conclusions: Rituximab pharmacodynamics was described in a real-world setting in children suffering from autoimmune and neurologic diseases. Diagnosis, substitution between innovator rituximab and its biosimilars or type of regimen did not affect rituximab-induced depletion of CD19+ nor the clinical response in this cohort of patients. According to this study, rituximab frequency and dosage may be chosen based on clinical convenience or safety reasons without affecting CD19+ repopulation times. Further studies in larger populations are required to confirm these results.

Keywords: NONMEM; biosimilar pharmaceuticals; paediatrics; pharmacodynamics; rituximab.

Figure 1

Schematic representation of the pharmacodynamic model describing the CD19+ depletion effects of rituximab. K_E, first-order rate constant of elimination; K_syn zero-order constant of CD19+ synthesis; K_deg, first-order rate constant of CD19+ elimination.

Figure 2

(A) Upper panel. Prediction-corrected visual predictive checks. The grey areas cover the 95% confidence intervals of the 2.5th, 50th and 97.5th percentiles calculated from the 500 simulated datasets. Lines represent the median (solid) and the 2.5th and 97.5th percentiles (dashed) of the raw data of the model-building dataset. Solid coloured circles show the data used to develop the model (red, neurologic diseases, blue, immune-haemato-rheumatologic diseases). Black circles correspond to the raw data from the cohort of patients used for external predictive performance evaluation (n = 11). Lower panel. The solid line represents the observed percentage of lower than the limit of quantification (LLOQ or below the limit of quantification, BLQ) values. The grey area covers the 95% confidence intervals of the simulations. Sticks on the x axis correspond to bins: (−147, −23, 22.5, 175, 300, and 600 days), (B) individual profiles of observed CD19+ cells (black points) and model predictions (grey lines and points) of four representative patients.

Figure 3

Individual predictions and simulations of the CD19+ B cell kinetics in a subgroup of patients (n = 7) in the first (pink lines) and in the second cycle of rituximab (blue lines), respectively. Individual observations are represented as circles. The horizontal dashed line represents the limit of quantification of CD19+ cells (10 × 10⁶ cells/L). Vertical dashed lines represent the rituximab infusions.

Figure 4

Simulated profiles of CD19+ B lymphocytes under three schemes frequently used in the clinics. Solid-black lines represent the median simulated values. Percentile bands of simulated data are represented in different shades of blue (level 90%, 9 bands).