Li Ziwei, Shen Qian, Xu Hong, Li Zhiping
Department of Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Department of Nephrology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Front Pharmacol. 2025 Jan 7;15:1526936. doi: 10.3389/fphar.2024.1526936. eCollection 2024.
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.
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 kinetic-pharmacodynamic (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.
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; = 0.026). The K-PD model predicted t (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. 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.
利妥昔单抗已被证明对特发性肾病综合征（INS）患儿有效。然而，绝大多数患儿在B细胞恢复后不可避免地会复发，需要重复使用利妥昔单抗疗程，这可能会增加不良反应的风险。INS患儿中利妥昔单抗额外给药的时机和可选给药方案尚未确定。本研究旨在确定影响疾病复发和B细胞恢复的因素，以提供个性化治疗。
对143名儿童进行LASSO和随机生存森林分析，以筛选协变量，然后将其纳入Cox回归模型，以确定复发的生物标志物并建立列线图。在59名儿童中建立了一个动力学-药效学（K-PD）模型，以表征利妥昔单抗治疗后CD19 B细胞的时间进程。进行蒙特卡洛模拟以探索更大间隔的小剂量方案。
列线图包含7个复发预测因子，包括中性粒细胞与淋巴细胞比率、B细胞耗竭持续时间、疾病持续时间、尿免疫球蛋白G与肌酐比率、尿转铁蛋白、维持免疫抑制剂持续时间和血红蛋白。作为直接的药效学指标，B细胞耗竭持续时间每增加1个月，复发风险降低21.4%（HR = 0.786；95% CI：0.635 - 0.972；P = 0.026）。K-PD模型预测利妥昔单抗和CD19 B细胞的t（CV%）分别为11.6天（17%）和173.3天（22%）。免疫球蛋白A是效应部位药物浓度（ED）的重要协变量。模拟更大间隔的小剂量方案（每2个月3次150mg）表明，与标准方案相比，B细胞耗竭时间更长（>7个月）。
列线图显示了复发前的最佳输注时机，K-PD模型为INS患儿提供了个性化的利妥昔单抗方案，以降低安全风险和经济负担。
