Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
Postdoctoral Research Station of Clinical Medicine and Department of Paediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
Br J Clin Pharmacol. 2023 Dec;89(12):3637-3647. doi: 10.1111/bcp.15868. Epub 2023 Aug 21.
Methotrexate (MTX) is recognized for its potential to induce hepatotoxicity, commonly manifested by elevated alanine aminotransferase (ALT) levels. However, the quantitative relationship between the pharmacokinetics (PK) of MTX and ALT-based hepatotoxicity remains unclear. This study aimed to develop a semimechanistic PK/pharmacodynamic (PD) model to characterize the MTX-induced hepatotoxicity based on ALT in paediatric patients with acute lymphoid leukaemia.
A retrospective study was conducted on paediatric patients who received high-dose (3-5 g/m ) MTX treatment. MTX concentrations were assessed at 24-h intervals until the concentration dropped below 0.1 μmol/L. ALT concentrations were measured both before and after MTX administration. A population PK model was initially developed, which was later connected to a semimechanistic hepatotoxicity model.
The PK model was developed using 354 MTX concentrations obtained from 51 patients, while the PD model was constructed using 379 ALT concentrations collected from 48 patients. The optimal PK model for MTX consisted of a 2-compartment structure, where body surface area served as a covariate for clearance and central volume of distribution. An indirect response model coupled to a liver injury signal transduction model was developed to describe the dynamics of ALT after MTX administration. The drug effect was adequately described by a linear model, exhibiting considerable interoccasion variability for each treatment session. No significant covariates were identified to have an impact on the PD parameters.
A semimechanistic model was developed to describe ALT-based hepatotoxicity of MTX, and it has the potential to serve as a valuable tool for characterizing drug-induced hepatotoxicity.
甲氨蝶呤（MTX）具有诱导肝毒性的潜力，通常表现为丙氨酸氨基转移酶（ALT）水平升高。然而，MTX 的药代动力学（PK）与基于 ALT 的肝毒性之间的定量关系尚不清楚。本研究旨在开发一种半机械 PK/药效动力学（PD）模型，以表征小儿急性淋巴细胞白血病患者 MTX 诱导的肝毒性。
对接受高剂量（3-5 g/m ）MTX 治疗的小儿患者进行回顾性研究。在浓度降至 0.1 μmol/L 以下之前，每 24 小时评估一次 MTX 浓度。在 MTX 给药前后测量 ALT 浓度。最初开发了一个群体 PK 模型，然后将其连接到半机械肝毒性模型。
该 PK 模型使用 51 名患者的 354 个 MTX 浓度进行开发，而 PD 模型则使用 48 名患者的 379 个 ALT 浓度进行构建。MTX 的最佳 PK 模型由 2 隔室结构组成，其中体表面积是清除率和中央分布容积的协变量。建立了一个间接反应模型，与肝损伤信号转导模型耦合，以描述 MTX 给药后 ALT 的动力学。药物效应通过线性模型得到很好的描述，每个治疗期都表现出相当大的间变可变性。未确定任何有意义的协变量对 PD 参数有影响。
开发了一种半机械模型来描述 MTX 基于 ALT 的肝毒性，它有可能成为表征药物诱导肝毒性的有用工具。
