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中国临床药理学与治疗学 ›› 2025, Vol. 30 ›› Issue (1): 70-77.doi: 10.12092/j.issn.1009-2501.2025.01.008

• 临床药理学 • 上一篇    下一篇

甲氨蝶呤在多种儿童肿瘤患者中的群体药代动力学研究

龚妍1,2,龚卫静1,2,李嘉欣1,2,秦琰杰1,2,罗立1,2   

  1. 1华中科技大学  同济医学院  附属协和医院  药学部,武汉  430022,湖北;2湖北省重大疾病精准用药临床医学中心,武汉  430022,湖北
  • 收稿日期:2024-04-11 修回日期:2024-05-17 出版日期:2025-01-26 发布日期:2025-01-02
  • 通讯作者: 罗立,男,硕士,副主任药师,主要从事临床药理学和药物治疗管理学的相关研究。 E-mail:764745900@qq.com
  • 作者简介:龚妍,女,硕士,主管药师,主要从事群体药代动力学建模和临床药理的相关研究。 E-mail:894367034@qq.com
  • 基金资助:
    国家自然科学基金项目(82003868)

Population pharmacokinetics of high-dose methotrexate in pediatric patients with diverse malignancies

GONG Yan1,2, GONG Weijing1,2, LI Jiaxin1,2, QIN Yanjie1,2, LUO Li1,2   

  1. 1 Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China; 2 Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, Hubei, China
  • Received:2024-04-11 Revised:2024-05-17 Online:2025-01-26 Published:2025-01-02

摘要:

目的:建立大剂量甲氨蝶呤在多种儿童肿瘤患者中的群体药代动力学(population pharmacokinetic,PPK)模型。方法:采用非线性混合效应模型法建立甲氨蝶呤PPK模型,患儿体表面积(body surface area,BSA)纳入采用异速增长模型。结果:最终模型为二室模型,血浆药物清除率(clearance,CL)群体典型值为4.51 L/(h·1.73 m2),中央室表观分布容积(apparent volume of distribution,Vd)群体典型值为15.47 L/1.73 m2;最终模型保留了患儿年龄、BSA、血肌酐(serum creatine,SCr)以及ABCC2 rs717620、ABCC4 rs2274407遗传变异这几个协变量。结论:患儿年龄、BSA、SCr以及ABCC2 rs717620、ABCC4 rs2274407基因型是影响儿童肿瘤患者体内甲氨蝶呤代谢的显著性因素。

关键词: 甲氨蝶呤, 儿童肿瘤, 群体药代动力学, 基因多态性

Abstract:

AIM: To establish a population pharmacokinetic (PPK) model of high-dose methotrexate in pediatric patients with diverse malignancies. METHODS: The PPK model of methotrexate was developed using non-linear mixed-effects model; body surface area (BSA) was incorporated by allometric size modelling. RESULTS: A two-compartment linear model best fitted the concentration data, typical values for clearance (CL) and central compartment distribution volume (Vd) were revealed to be 4.51 L/(h·1.73 m2) and 15.47 L/1.73 m2, respectively. Age, BSA, serum creatinine (SCr) and genotypes of ABCC2 rs717620 and ABCC4 rs2274407 were retained in the final model. CONCLUSION: Age, BSA, SCr and genotypes of ABCC2 rs717620 and ABCC4 rs2274407 were identified to be significantly affecting the clearance. 

Key words: methotrexate, pediatric malignancies, population pharmacokinetics, genetic polymorphism

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