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中国临床药理学与治疗学

• 生物药研发 • 上一篇    下一篇

HER2阳性乳腺癌辅助治疗中帕妥珠单抗和曲妥珠单抗的个体化给药研究

马培敏1,付 毓 2,Marcus VETTER 3   

  1. 1葛兰素史克(上海)公司,上海 201203;2北京大学药学院,北京 100871;3巴塞尔大学医院,巴塞尔 4031,瑞士
  • 收稿日期:2019-10-08 修回日期:2019-12-20 出版日期:2020-01-26 发布日期:2020-02-11
  • 作者简介:马培敏,男,博士,高级总监,GSK高级研究员,研究方向:中国药物研发以及定量药理和药动药效学在研发中的应用。 Tel:+86(21)6159-0580E-mail:peiming.p.ma@gsk.com 付毓,女,硕士,研究方向:定量系统药理学在心血管系统中的应用。 Tel:18811331596E-mail:yufu@pku.edu.cn Marcus VETTER,男,博士,主任医师,研究方向:乳腺癌的治疗。 E-mail:Marcus.Vetter@usb.ch

Personalizing pertuzumab and trastuzumab dosing regimens for adjuvant treatment of HER2-positive breast cancer

MA Peiming 1, FU Yu 2, Marcus VETTER 3   

  1. 1 Clinical Pharmacology Modeling and Simulation GlaxoSmithKline, Shanghai 201203, China; 2 Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China; 3 Department of Medical Oncology, University Hospital Basel 4031 Basel, Switzerland
  • Received:2019-10-08 Revised:2019-12-20 Online:2020-01-26 Published:2020-02-11

摘要: 目的:为一个亚裔早期乳腺癌患者制定并实施曲妥珠和帕妥珠单抗的个体化治疗方案。方法:曲妥珠和帕妥珠单抗是HER2阳性乳腺癌患者的重要治疗药物。尽管药动学相似,但推荐的给药方案不同:帕妥珠单抗为固定剂量,而曲妥珠单抗剂量取决于体重;帕妥珠单抗给药为每三周一次,但曲妥珠单抗给药为每周一次或每三周一次。当两种药与化药物合并使用时,执业医师对给药方案的选择有限。剂量-暴露量-效应关系是决定给药方案的重要依据。为了解个体患者的剂量-暴露量-效应关系,我们审查了群体药动学分析文献以了解对暴露量有影响的协变量(疾病状态和体重等),另外考虑了有效和安全性因素如最低有效性浓度,亚洲患者的不良事件发生率,及给药方便性等。结果:基于对帕妥珠和曲妥珠单抗的群体药动学及药动和协变量关系的了解,对该患者制定并实施了曲妥珠和帕妥珠单抗的每两周一次的个体化给药方案。结论:个体化给药方案的制定需个体化剂量-暴露量-效应关系支持,而群体分析是了解个体化剂量-暴露量-效应关系的重要工具。

关键词: 个体化给药方案, 曲妥珠单抗, 帕妥珠单抗, 药动学

Abstract: AIM: To design and implement personalized dosing regimens of trastuzumab and pertuzumab for an Asian patient with early breast cancer. METHODS: Trastuzumab and pertuzumab are important therapeutics for patients with HER2-positive breast cancer. Despite the similar pharmacokinetics (PK), their recommended dosing regimens differ: pertuzumab dosing is fixed whereas trastuzumab dosing depends on body weight; the dosing frequency is once every three weeks for pertuzumab but includes both once every week (QW) and once every three weeks (Q3W) for trastuzumab. A practicing physician has limited choices for dosing regimens when using the drugs in combination with chemotherapies. Besides convenience in drug administration, efficacy and safety as responses to the drug must be examined as part of studying dose-exposure-response relationship, which is the basis for deciding a dosing regimen. To understand the dose-exposure-response relationship of an individual patient, we reviewed literature on population PK analyses. The associated PK-covariate relationships including influential covariates such as disease status and demographics (e.g., body weight) that informed the patients underlying dose-exposure-response relationships. Safety and efficacy factors essential for choosing appropriate dosing regimens were also considered — minimal target concentrations, higher adverse event rates in Asian patients, as well as administration convenience. RESULTS:Based on a thorough review of population PK and PK-covariate relationships of pertuzumab and trastuzumab, an individualized dosing regimen of once every two weeks (Q2W) was selected as the treatment option and implemented for this patient. CONCLUSION: The design of an individualized dosing regimen requires the knowledge of individualized dose-exposure-response relationships, and population analysis is an ideal tool for understanding the individualized dose-exposure-response relationships.

Key words: personalized dosing regimen, pertuzumab, trastuzumab, pharmacokinetics

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