摘要
目的建立大剂量甲氨蝶呤(HDMTX)在血液肿瘤患儿中的群体药代动力学(PPK)模型,分析甲氨蝶呤(MTX)清除和分布的主要影响因素,探讨儿童HDMTX疗法的个体化用药方案。方法收集南京医科大学附属儿童医院2021年1月1日至2023年12月31日间收治并采用HDMTX治疗血液系统恶性肿瘤患儿的一般资料、诊断治疗信息及实验室指标,使用非线性混合效应模型法建立PPK模型,采用一级消除的二房室模型描述MTX的药代动力学特征,使用逐步法进行协变量筛选,通过拟合优度图、自举法、校正预测的可视化预测检验对最终模型进行内部验证。基于最终模型进行剂量模拟及临床场景设计,使用蒙特卡洛模拟法考察不同给药方案下不发生MTX排泄延迟的达标率(PTA),并以此筛选出合适的个体化用药方案。结果最终模型显示,MTX中央室和周围室的表观清除率群体典型值分别为6.17 L·h^(-1)和0.13 L·h^(-1),体表面积(BSA)是MTX清除率的主要影响因素。验证结果表明最终模型具有良好的预测性能及稳定性。基于该模型,为接受HDMTX治疗的儿童制定了针对不同体表面积特征的剂量方案。结论本研究建立了儿童MTX的PPK模型,并基于该模型制定了体表面积-总药量个体化用药方案,改善经HDMTX治疗患儿的治疗结局。
Objective To establish a population pharmacokinetic(PPK)model for high-dose methotrexate(HDMTX)in pediatric patients with hematologic malignancies,identify covariates affecting MTX clearance and distribution,and explore individualized dosing strategies for HDMTX therapy in children.Methods Demographic data,diagnostic and treatment information,and laboratory parameters were retrospectively collected from pediatric HDMTX chemotherapy courses at the Children’s Hospital of Nanjing Medical University between January 1,2021,and December 31,2023.A PPK model was developed using nonlinear mixed-effects modeling(NONMEM).The pharmacokinetic characteristics of MTX were described by a two-compartment model with first-order elimination.Stepwise covariate modeling was performed,and the final model was internally validated using goodness-of-fit diagnostics,bootstrap analysis,and prediction-corrected visual predictive checks.Based on the final model,dosing simulations under multiple clinical scenarios were performed.Monte Carlo simulation was applied to evaluate the probability of achieving target exposure and preventing delayed MTX elimination across various dosing regimens and clinical scenarios,aiming to identify optimal individualized dosing strategies.Results The final model estimated typical population values for the apparent clearance of MTX in the central and peripheral compartments as 6.17 L·h^(-1)and 0.13 L·h^(-1),respectively.Body surface area(BSA)was identified as the principal determinant of MTX clearance.Validation results indicated that the final model exhibited strong predictive performance and stability.Based on this model,BSA-stratified dosing regimens were refined for pediatric patients receiving HDMTX therapy.Conclusion This study established a PPK model for MTX in children using a large sample and developed BSA-based individualized dosing strategies to optimize treatment outcomes for pediatric patients receiving HDMTX therapy.
作者
周城羽
万瑜
薛瑶
李玥
戎留成
陈峰
方拥军
葛许华
ZHOU Chengyu;WAN Yu;XUE Yao;LI Yue;RONG Liucheng;CHEN Feng;FANG Yongjun;GE Xuhua(Pediatric Intensive Care Unit,Children’s Hospital of Nanjing Medical University,Nanjing 210019,China;Department of Pediatrics,The Second People’s Hospital of Changzhou,The Third Affiliated Hospital of Nanjing Medical University,Changzhou 213000,China;Department of Hematology,Children’s Hospital of Nanjing Medical University,Nanjing 210019,China;Department of Pharmacy,Children’s Hospital of Nanjing Medical University,Nanjing 210019,China;Jiangsu Key Laboratory of Children’s Major Disease Research,Children’s Hospital of Nanjing Medical University,Nanjing 210019,China)
出处
《中国医科大学学报》
北大核心
2026年第2期115-121,共7页
Journal of China Medical University
基金
国家自然科学基金(82170733)
常州市卫健委科技项目(QN202316)。
关键词
甲氨蝶呤
群体药代动力学
儿童
血液系统恶性肿瘤
排泄延迟
建模及模拟
个体化用药
methotrexate
population pharmacokinetics
pediatrics
hematologic malignancies
delayed elimination
modeling and simu-lation
precision medicine
