Using real-world data to inform dosing strategies of rituximab for pediatric patients with frequent-relapsing or steroid-dependent nephrotic syndrome: a prospective pharmacokinetic-pharmacodynamic study

Abstract

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). However, the optimal dosing schedules remain undetermined. The objective of this study was to establish a population pharmacokinetic-pharmacodynamic (PK-PD) model in pediatric patients with FRNS/SDNS, and to investigate dosing regimens that provide adequate suppression of B lymphocytes. Methods: A prospective, open-label, single-center study was conducted in Nephrology Department at Children's Hospital of Fudan University, and a two-compartment PK model of rituximab in pediatric FRNS/SDNS has been developed previously by our group. CD19⁺ lymphocyte count profiles were obtained from these patients. The presence of anti-rituximab antibodies was assessed prior to medication in children who had previously received rituximab or during follow-up at the last sampling point for PK analysis. PK-PD analyses were performed to describe the changes of CD19⁺ lymphocytes, with rituximab assumed to increase their death rate. Monte Carlo simulation was conducted to evaluate different dosing regimens. Results: In total, 102 measurements of CD19⁺ lymphocyte counts were available for PK-PD analysis. No detectable levels of anti-rituximab antibodies were observed during the PK follow-up period. A turnover model with saturable stimulatory action of rituximab on the removal of lymphocytes best characterized the relationship between rituximab concentration and CD19⁺ lymphocyte counts, where the E_max and EC₅₀ were estimated to be 99.6*10⁶/L and 5.87 μg/mL, respectively. Simulations indicated that a single infusion of 750 mg/m² and 2 infusions of 375 mg/m² both yielded a 10-week suppression of CD19⁺ lymphocytes. Conclusion: This study represents a first attempt to quantitatively describe the PK-PD relationship of rituximab in pediatric patients with FRNS/SDNS, and provide a potential pathway for future precision dosing strategy for rituximab therapy. Further clinical studies are warranted to evaluate the efficacy and safety of different dosing schemes.

Keywords: nephrology; pediatric; pharmacodynamics; pharmacokinetics; precision medicine.

FIGURE 1

Schematic representation of rituximab pharmacokinetic-pharmacodynamic model. k₁₂, elimination rate constant from the central compartment to peripheral compartment; k₂₁, elimination rate constant from the peripheral compartment to central compartment; k_e, elimination rate constant of rituximab; k_in, production rate of CD19⁺ lymphocytes; k_out, elimination rate constant of CD19⁺ lymphocytes; plus sign, promotion on CD19⁺ lymphocytes elimination.

FIGURE 2

Individual serum rituximab concentrations and CD19⁺ counts with time profiles. (A) Plots after the first dose. (B) Plots after the last dose. Closed circles represent rituximab concentrations previously reported in our study (Chen et al., 2021), while open circles represent CD19⁺ counts. Black circles represent patients receiving two infusions of rituximab, and red circles represent patients receiving only one infusion.

FIGURE 3

Goodness-of-fit plots of rituxiamb final PK-PD model. (A) The observed versus population-predicted concentration. (B) The observed versus individual-predicted concentration. (C) Conditional weighted residual versus time. (D) Conditional weighted residual versus the predicted concentration. (E) The observed versus population-predicted CD19⁺ lymphocyte count. (F) The observed versus individual-predicted CD19⁺ lymphocyte count. (G) Conditional weighted residual versus time. (H) Conditional weighted residual versus the predicted CD19⁺ lymphocyte count.

FIGURE 4

Prediction-corrected visual predictive check of the final PK-PD model. Circles represent the observed concentrations (rituximab concentrations have been reported in our previous study (Chen et al., 2021)). Solid lines represent the observed median, 10th and 90th percentiles of observed profiles. The shaded areas correspond to the simulation-based 95% confidence intervals.

FIGURE 5

Simulated profiles of suppression of CD19⁺ lymphocytes after variable dosing regimen of rituximab (red: a single infusion of 100 mg/m², purple: a single infusion of 375 mg/m², green: 2 infusions of 375 mg/m² given 2 weeks apart, blue: four weekly infusions of 375 mg/m², gold: a single infusion of 750 mg/m², black: 2 infusions of 750 mg/m², grey band: 90% prediction interval).