Abstract：
Intractable lymphatic malformations (iLM) pose a significant threat to affected children, demonstrating limited responses to conventional treatments. Sirolimus, effectively inhibiting endothelial cell proliferation in lymphatic vessels, plays a crucial role in iLM treatment. However, the drug\'s narrow therapeutic window and substantial interindividual variability necessitate customized dosing strategies. This study aims to establish a Population Pharmacokinetic Model (PopPK model) for sirolimus in pediatric iLM patients, identifying quantitative relationships between covariates and sirolimus clearance and volume of distribution. Initial dosages are recommended based on a target concentration range of 5-15 ng/mL. Retrospective data from our institution, encompassing 53 pediatric patients with 275 blood concentration results over the past five years (average age: 4.64 ± 4.19 years), constituted the foundation of this analysis. The final model, adopting a first-order absorption and elimination single-compartment model, retained age as the sole covariate. Results indicated a robust correlation between apparent clearance (CL/F) at 5.56 L/h, apparent volume of distribution (V/F) at 292.57 L, and age. Monte Carlo simulation guided initial dosages for patients aged 0-18 years within the target concentration range. This study presents the first PopPK model using a large Therapeutic Drug Monitoring (TDM) database to describe personalized sirolimus dosing for pediatric iLM patients, contributing to pharmacokinetic guidance and potentially improving long-term clinical outcomes.
摘要：
顽固性淋巴畸形（iLM）对受影响的儿童构成重大威胁，对常规治疗的反应有限。西罗莫司,有效抑制淋巴管内皮细胞增殖，在iLM治疗中起着至关重要的作用。然而,该药物狭窄的治疗窗口和显著的个体间差异需要定制的给药策略。本研究旨在建立儿童iLM患者西罗莫司的群体药代动力学模型(PopPK模型),确定协变量与西罗莫司清除率和分布量之间的定量关系。基于5-15ng/mL的目标浓度范围推荐初始剂量。我们机构的回顾性数据，包括53名儿科患者，在过去五年中有275名血液浓度结果（平均年龄：4.64±4.19岁），构成了这一分析的基础。最终的模型，采用一阶吸收和消除单室模型，保留年龄作为唯一的协变量。结果表明，在5.56L/h时，表观清除率(CL/F)之间存在密切的相关性，292.57L时的表观分布体积（V/F），和年龄。蒙特卡罗模拟指导0-18岁患者在目标浓度范围内的初始剂量。这项研究提出了第一个使用大型治疗药物监测（TDM）数据库来描述儿科iLM患者个性化西罗莫司给药的PopPK模型。有助于药代动力学指导并可能改善长期临床结果。
