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

Yewei Chen; Qian Shen; Ye Xiong; Min Dong; Hong Xu; Zhiping Li

doi:10.3389/fphar.2023.1319744

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

Front Pharmacol. 2024 Jan 9:14:1319744. doi: 10.3389/fphar.2023.1319744. eCollection 2023.

Authors

Yewei Chen^#¹, Qian Shen^#², Ye Xiong³, Min Dong^{3

4}, Hong Xu², Zhiping Li¹

Affiliations

¹ Department of Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
² Department of Nephrology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
³ Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
⁴ Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States.

^# Contributed equally.

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.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Wu Jieping Medical Foundation (320.6750.19090-38).