中国医科大学学报2026，Vol.55Issue(2)：115-121,7.DOI:10.12007/j.issn.0258-4646.2026.02.004
体表面积对血液系统恶性肿瘤患儿大剂量甲氨蝶呤排泄延迟影响的群体药代动力学研究
Population pharmacokinetics on the impact of body surface area on delayed methotrexate elimination in children with hematologic malignancies receiving high-dose therapy
摘要
Abstract
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 mo-deling was performed,and the final model was internally validated using goodness-of-fit diagnostics,bootstrap analysis,and prediction-cor-rected 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 esti-mated 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.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Key words
methotrexate/population pharmacokinetics/pediatrics/hematologic malignancies/delayed elimination/modeling and simu-lation/precision medicine分类
医药卫生引用本文复制引用
周城羽,万瑜,薛瑶,李玥,戎留成,陈峰,方拥军,葛许华..体表面积对血液系统恶性肿瘤患儿大剂量甲氨蝶呤排泄延迟影响的群体药代动力学研究[J].中国医科大学学报,2026,55(2):115-121,7.基金项目
国家自然科学基金(82170733) （82170733）
常州市卫健委科技项目(QN202316) （QN202316）
