An interactive dose optimizer based on population pharmacokinetic study to guide dosing of methotrexate in Chinese patients with osteosarcoma.

IF 2.7 4区医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-11-01 Epub Date: 2024-08-24 DOI:10.1007/s00280-024-04708-x

Yanjie Zhang, Xiemin Qi, Xiaohui Huang, Xiaozhou Liu, Yanyu Liu, Jianzhong Rui, Qiong Yin, Sujia Wu, Guohua Zhou

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Abstract

Purpose: Osteosarcoma is a rare tumor with an incidence of 4.4 cases per million per year in adolescent. High-dose methotrexate (HD-MTX) is the standard first-line chemotherapeutic agent for osteosarcoma. However, its efficacy can vary significantly among individuals due to wide pharmacokinetic variability. Despite this, only a few population pharmacokinetics (popPK) models based on Chinese patients with osteosarcoma have been reported. Thus, this study aimed to develop a HD-MTX popPK model and an individual model-based dose optimizer for osteosarcoma therapy.

Method: A total of 680 MTX serum concentrations from 57 patients with osteosarcoma were measured at the end of MTX infusion and 10 h, 24 h, 48 h, and 72 h after the start of infusion. Using the first-order conditional estimation method with NONMEM, a popPK model was estimated. Goodness-of-fit plots, visual predictive checks, and bootstrap analysis were generated to evaluate the final model. A dose optimizer tool was developed based on the validated models using R Shiny. Additionally, clinical data from 12 patients with newly diagnosed osteosarcoma were collected and used as the validation set to preliminarily verify the predictive ability of the popPK model and the dose optimizer tool.

Results: Body surface area (BSA) was the most significant covariate for compartment distribution. Creatinine clearance (CrCL) and co-administration of NSAIDs were introduced as predictors for central compartmental and peripheral compartmental clearance, respectively. Co-administration of NSAIDs was associated with significantly higher MTX concentrations at 72 h (p = 0.019). The dose optimizer tool exhibited a high consistency in predicting MTX AUC compared to the actual AUC (r = 0.821, p < 0.001) in the validation set.

Conclusion: The dose optimizer tool could be used to estimate individual PK parameters, and optimize personalized MTX therapy in particular patients.

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基于群体药代动力学研究的交互式剂量优化器，用于指导中国骨肉瘤患者的甲氨蝶呤用药。

目的：骨肉瘤是一种罕见肿瘤，在青少年中的发病率为每年每百万人中4.4例。大剂量甲氨蝶呤（HD-MTX）是治疗骨肉瘤的标准一线化疗药物。然而，由于药代动力学的广泛变异性，其疗效在个体之间会有很大差异。尽管如此，基于中国骨肉瘤患者的群体药代动力学（popPK）模型却鲜有报道。因此，本研究旨在建立 HD-MTX popPK 模型和基于个体模型的骨肉瘤治疗剂量优化器：方法：在MTX输注结束时、输注开始后10小时、24小时、48小时和72小时测量了57名骨肉瘤患者的680个MTX血清浓度。利用 NONMEM 的一阶条件估计法，对 popPK 模型进行了估计。生成拟合优度图、视觉预测检查和引导分析来评估最终模型。根据验证过的模型，使用 R Shiny 开发了一个剂量优化工具。此外，还收集了 12 名新确诊骨肉瘤患者的临床数据作为验证集，以初步验证 popPK 模型和剂量优化工具的预测能力：体表面积（BSA）是影响分区分布的最重要的协变量。肌酐清除率（CrCL）和同时服用非甾体抗炎药分别是中心区室和外周区室清除率的预测因子。联合使用非甾体抗炎药与 72 小时内 MTX 浓度显著升高有关（p = 0.019）。与实际AUC相比，剂量优化工具在预测MTX AUC方面表现出较高的一致性（r = 0.821，p 结论）：剂量优化工具可用于估计个体 PK 参数，并优化特定患者的个性化 MTX 治疗。

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来源期刊

Cancer Chemotherapy and Pharmacology 医学-药学

CiteScore

6.10

自引率

3.30%

发文量

116

审稿时长

2.5 months

期刊介绍： Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.