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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Obstetric and Pediatric Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1526936
This article is part of the Research Topic Precision Medicine in Pediatrics - Volume II View all 14 articles

Kinetic-pharmacodynamic model to predict post-rituximab B-cell repletion as a predictor of relapse in pediatric idiopathic nephrotic syndrome

Provisionally accepted
Ziwei Li Ziwei Li Qian Shen Qian Shen Hong Xu Hong Xu *Zhiping Li Zhiping Li *
  • Children’s Hospital of Fudan University, National Children's Medical Center, Shanghai, China

The final, formatted version of the article will be published soon.

    Purpose: Rituximab has proven efficacy in children with idiopathic nephrotic syndrome (INS). However, vast majority of children inevitably experience relapse with B-cell repletion, necessitating repeat course of rituximab, which may increase the risk of adverse effects. The timing of additional dosing and optional dosing regimen of rituximab in pediatric patients with INS have yet to be determined. This study aimed to identify factors that influence disease relapse and B-cell repletion to provide tailored treatment.Methods: LASSO and random survival forest were performed on 143 children to screen covariates which were then included in Cox regression model to determine the biomarkers of relapse and establish a nomogram. A kineticpharmacodynamic (K-PD) model was developed in 59 children to characterize the time course of CD19 + B-cell after rituximab treatment. Monte Carlo simulation was conducted to explore a mini-dose regimen with larger intervals.Results: Nomogram contained 7 predictors of relapse including neutrophil-to-lymphocyte ratio, duration of B-cell depletion, duration of disease, urine immunoglobulin G to creatinine ratio, urine transferrin, duration of maintenance immunosuppressant and hemoglobin. As a direct PD indicator, each 1-month increase of duration of B-cell depletion decreased risk of relapse by 21.4% (HR = 0.786; 95% CI: 0.635-0.972; P = 0.026). The K-PD model predicted t 1/2 (CV%) of rituximab and CD19 + B-cell to be 11.6 days (17%) and 173.3 days (22%), respectively. Immunoglobulin A is an important covariate of ED 50 . Simulation of a mini-dose regimen with larger intervals (three 150 mg every 2 monthly) indicted longer B-cell depletion time (>7 months) compared to standard regimen.The nomogram indicated optimal infusion timing before relapse and the K-PD model provided tailored rituximab regimens for children with INS to reduce safety risks and financial burden.

    Keywords: rituximab, Idiopathic nephrotic syndrome, Kinetic-pharmacodynamic model, relapse, B-cell

    Received: 12 Nov 2024; Accepted: 17 Dec 2024.

    Copyright: © 2024 Li, Shen, Xu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Hong Xu, Children’s Hospital of Fudan University, National Children's Medical Center, Shanghai, China
    Zhiping Li, Children’s Hospital of Fudan University, National Children's Medical Center, Shanghai, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.