Population pharmacokinetic model of high-dose methotrexate in Chinese patients with Intracranial germ cell tumors

Jiashu Zhao¹Ruoyun Wu^2,3Sitian Zhang⁴Qian Lu⁵Ruitao Wang¹Yingjun He^5*Zhigang Zhao^2,3*Shenghui Mei^2,3*

• ¹Department of Pharmacy, Beijing Puren Hospital, Dongcheng, Beijing Municipality, China
• ²Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, Beijing, China
• ³Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
• ⁴School of Basic Medical Sciences, Capital Medical University, Beijing, Beijing Municipality, China
• ⁵Department of Pharmacy, Bijie Maternal and Child Health Hospital, Bijie, China

This study aims to investigate the pharmacokinetics of MTX (methotrexate) 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 interindividual variability and a proportional residual model was established using nonlinear mixed-effects modeling. The model was based on 5470 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 𝐶𝐿 = 12.88 × (𝑒𝐺𝐹𝑅/102.2) 0.23 × (𝐵𝑊/47) 0.39 × 𝑒 𝐵𝐿𝑀 × (𝑇𝐵𝐼𝐿/15.3) -0.05 × (𝐴𝐿𝐵/40.9) -0.18 (BLM = 0.08 when combined with bleomycin, otherwise = 0). The apparent volume of the central compartment (Vc) was V c = 72.04×(BW/47) 0.31 . The apparent volumes of the peripheral compartments (Vp) and the inter-compartmental clearance (Q) were fixed as 94.94 L and 1.08 L/h and, 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.