Research progress in pharmacokinetics and therapeutic drug monitoring of tyrosine kinase inhibitors in the treatment of gastrointestinal stromal tumors

HUANG Qiongye; ZHAO Yang; LIU Yi; WANG Yongqing; SUN Luning

doi:10.6039/j.issn.1001-0408.2024.07.22

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Research progress in pharmacokinetics and therapeutic drug monitoring of tyrosine kinase inhibitors in the treatment of gastrointestinal stromal tumors

更新时间：2025-09-25

- Research progress in pharmacokinetics and therapeutic drug monitoring of tyrosine kinase inhibitors in the treatment of gastrointestinal stromal tumors
- ZHONGGUO YAOFANG Vol. 35, Issue 7, Pages: 890-895(2024)
- 作者机构：
  
  1.南京医科大学第一附属医院临床药理中心，南京　210029
  2.南京医科大学药学院，南京　211166
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2024.07.22
  CLC： R969;R979.1
- Received：21 October 2023，
  
  Revised：2024-02-04，
  
  Accepted：24 February 2024，
  
  Published：15 April 2024
- 稿件说明：
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黄琼叶,赵杨,刘仪,等.酪氨酸激酶抑制剂治疗胃肠间质瘤的药动学和治疗药物监测研究进展[J].中国药房,2024,35(07):890-895.

HUANG Qiongye,ZHAO Yang,LIU Yi,et al.Research progress in pharmacokinetics and therapeutic drug monitoring of tyrosine kinase inhibitors in the treatment of gastrointestinal stromal tumors[J].ZHONGGUO YAOFANG,2024,35(07):890-895.
黄琼叶,赵杨,刘仪,等.酪氨酸激酶抑制剂治疗胃肠间质瘤的药动学和治疗药物监测研究进展[J].中国药房,2024,35(07):890-895. DOI： 10.6039/j.issn.1001-0408.2024.07.22.

HUANG Qiongye,ZHAO Yang,LIU Yi,et al.Research progress in pharmacokinetics and therapeutic drug monitoring of tyrosine kinase inhibitors in the treatment of gastrointestinal stromal tumors[J].ZHONGGUO YAOFANG,2024,35(07):890-895. DOI： 10.6039/j.issn.1001-0408.2024.07.22.

摘要

酪氨酸激酶抑制剂（TKIs）是一类小分子靶向药物，可改善胃肠间质瘤（GIST）患者的生存时间。伊马替尼、舒尼替尼、瑞戈非尼、瑞派替尼、阿伐替尼是临床治疗不同类型GIST的常用TKIs。本文对这5种药物的药动学和治疗药物监测（TDM）研究进展进行综述，发现该类药物的药动学个体差异大，其中伊马替尼、瑞戈非尼、阿伐替尼的吸收受食物影响，因此建议患者随餐服用伊马替尼并饮水200 mL，随低脂餐服用瑞戈非尼，空腹服用阿伐替尼。TKIs主要由细胞色素P450 3A4酶（CYP3A4）进行代谢，与CYP3A4诱导剂或抑制剂合用时，药物暴露量会产生明显改变；除代谢酶外，TKIs的暴露量也受转运体P-糖蛋白和乳腺癌耐药蛋白影响。目前对于TKIs的TDM研究仍处在探索阶段，伊马替尼、舒尼替尼、瑞戈非尼的有效浓度虽然已有相关文献依据，但其暴露量与疗效/毒性之间的确切关系有待进一步研究。瑞派替尼和阿伐替尼目前缺乏暴露量与疗效/毒性的相关研究，建议对服用上述药物的患者实施TDM并结合药动学模型探索其治疗窗。目前常用于TKIs临床TDM的检测方法包括免疫法、色谱法和表面增强拉曼光谱法，为明确TKIs的治疗窗提供了技术基础。

Abstract

Tyrosine kinase inhibitors （TKIs） represent a class of small-molecule targeted drugs that improve the survival time of patients with gastrointestinal stromal tumor （GIST）. Imatinib， sunitinib， regorafenib， ripretinib， and avapritinib are commonly used TKIs in the clinical treatment of various types of GIST. This article provides a comprehensive review of the pharmacokinetics and therapeutic drug monitoring （TDM） of these five drugs， finding that there is significant individual variability in the pharmacokinetics of these drugs. Among them， the absorption of imatinib， regorafenib， and avapritinib are influenced by food intake. Imatinib should be taken with meals and 200 mL of water， regorafenib is taken with a low-fat meal， while avapritinib is taken on an empty stomach. TKIs are mainly metabolized by cytochrome P450 3A4 （CYP3A4）， and when used in combination with CYP3A4 inducers or inhibitors， drug exposure levels will significantly change； apart from metabolic enzymes， the exposure levels of TKIs are also influenced by interactions with the transporter proteins P-glycoprotein and breast cancer resistance protein. Currently， research on TDM for TKIs is still in the exploratory stage， with a substantial amount of literature reporting the effective concentrations of imatinib， sunitinib and regorafenib. However， the precise relationship between exposure levels and efficacy/toxicity needs further exploration. Currently， there is a lack of research on the correlation between exposure levels and efficacy/toxicity of ripretinib and avapritinib. It is recommended to implement TDM in patients taking these drugs and explore their therapeutic window in combination with pharmacokinetic models. The commonly used methods for clinical TDM of TKIs include immunoassay， chromatography， and surface-enhanced Raman spectroscopy， providing a technical basis for clarifying the therapeutic window of TKIs.

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references

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