Zhao Jiashu, Wu Ruoyun, Zhang Sitian, Lu Qian, Wang Ruitao, He Yingjun, Zhao Zhigang, Mei Shenghui
Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Department of Pharmacy, Beijing Puren Hospital, Beijing, China.
Front Pharmacol. 2025 May 2;16:1548203. doi: 10.3389/fphar.2025.1548203. eCollection 2025.
This study aims to investigate the pharmacokinetics of methotrexate (MTX) in Chinese patients with intracranial germ cell tumors (iGCTs) and to develop a robust population pharmacokinetic (PPK) model. A two-compartment model with an exponential inter-individual variability and a proportional residual model was established using nonlinear mixed-effects modeling. The model was based on 5,470 plasma concentration data points from 505 Chinese iGCT patients, including 370 children. The impact of covariates on model parameters was evaluated using forward addition and backward elimination strategies. Goodness-of-fit plots, bootstrap, visual predictive check and normalized prediction distribution errors were used to assess model performance. In the final model, the clearance of the central compartment (CL) was determined using the following equation (BLM = 0.08 when combined with bleomycin, otherwise = 0). The apparent volume of the central compartment (V) was . The apparent volumes of the peripheral compartments (V) and the inter-compartmental clearance (Q) were fixed as 94.94 L and 1.08 L/h, respectively. Co-administration with bleomycin could increase MTX CL by a factor of 1.08. Elevated total bilirubin and albumin levels were associated with decreased MTX CL. Goodness-of-fit and model evaluation confirmed the final model's adequacy, stability, and predictive performance. In our study, a PPK model was developed to identify the key factors influencing MTX pharmacokinetics, thereby optimizing and personalizing MTX therapy for Chinese patients with iGCTs.
本研究旨在调查甲氨蝶呤（MTX）在中国颅内生殖细胞肿瘤（iGCTs）患者中的药代动力学，并建立一个稳健的群体药代动力学（PPK）模型。使用非线性混合效应建模建立了一个具有指数个体间变异性和比例残差模型的二室模型。该模型基于505例中国iGCT患者（包括370名儿童）的5470个血浆浓度数据点。使用向前添加和向后消除策略评估协变量对模型参数的影响。使用拟合优度图、自助法、视觉预测检查和标准化预测分布误差来评估模型性能。在最终模型中，中央室清除率（CL）使用以下公式确定（与博来霉素联合使用时BLM = 0.08，否则 = 0）。中央室的表观容积（V）为 。外周室的表观容积（V）和室间清除率（Q）分别固定为94.94 L和1.08 L/h。与博来霉素联合使用可使MTX的CL增加1.08倍。总胆红素和白蛋白水平升高与MTX的CL降低有关。拟合优度和模型评估证实了最终模型的充分性、稳定性和预测性能。在我们的研究中，开发了一个PPK模型以确定影响MTX药代动力学的关键因素，从而优化并个体化中国iGCT患者的MTX治疗。
