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中国临床药理学与治疗学 ›› 2019, Vol. 24 ›› Issue (4): 418-423.doi: 10.12092/j.issn.1009-2501.2019.04.009

• 定量药理学 • 上一篇    下一篇

乳腺癌患者体内他莫昔芬的群体药代动力学研究

吴 敏1,过怿赟2,谢海棠2   

  1. 1芜湖市第二人民医院药耗供应部,芜湖 241001,安徽; 2皖南医学院弋矶山医院临床药学部,芜湖 241001,安徽
  • 收稿日期:2018-11-26 修回日期:2018-12-13 出版日期:2019-04-26 发布日期:2019-05-01
  • 通讯作者: 谢海棠,女,博士,研究员,教授,硕士生导师,研究方向为定量药理学与临床药代动力学。 Tel:13855389779 E-mail:xiehaitang@sina.com
  • 作者简介:吴敏,女,本科,主管药师,主要从事医院药学方向研究。 Tel:18055316014 E-mail:wu_min911@hotmail.com
  • 基金资助:

    国家自然科学基金资助项目(81173134);皖南医学院中青年科研基金资助项目(WK2015F11)

Population pharmacokinetics of tamoxifen in patients with breast cancer

WU Min 1, GUO Yiyun 2, XIE Haitang 2   

  1. 1 Department of Drug and Consumable Supply, the Second People's Hospital of Wuhu, Wuhu 241001, Anhui, China; 2 Department of Clinical Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu 241001, Anhui, China
  • Received:2018-11-26 Revised:2018-12-13 Online:2019-04-26 Published:2019-05-01

摘要:

目的:考察他莫昔芬(TAM)在乳腺癌患者体内的药物代谢动力学特征,以及可能的影响因素。方法:采集规律服用TAM的乳腺癌患者的血液样本,使用HPLC-MS/MS测定TAM及其代谢产物Endoxifen的血药浓度,以非线性混合效应模型法(NONMEM)进行分析,得到群体药代动力学参数,与文献中TAM药代动力学参数进行比较,并用Bootstrap对最终模型进行验证。结果:共29例患者参加该研究,平均年龄(46.9±6.4)岁,体质量指数(BMI)为(23.70±2.87) kg/cm2。最终模型的药代动力学参数估计值分别为,Ka为0.830 h-1;CLTAM为6.61 L/h;CLMET为0.707 L/h;VTAM为753 L;VEND为400 L;CLEND为5.10 L/h;Q为61.8 L。协变量筛选,在向前包容过程中显示有机阴离子转运多肽OATP1B1*521的基因多态性和绝经时间对代谢常数CLTAM有影响(P<0.05),但向后剔除过程未发现有显著性影响的协变量(P<0.001)。Bootstrap结果显示最终模型稳健率达96.8%。结论:本研究成功构建了TAM在乳腺癌患者体内的群体药代动力学模型,并从定量的角度为TAM临床个体化用药提供参考信息。

关键词: 他莫昔芬, 乳腺癌, 群体药代动力学, OATP1B1

Abstract:

AIM:To investigate the population pharmacokinetic characteristics of tamoxifen (TAM) in breast cancer patients and factors that might impact its clearance. METHODS: Blood samples of breast cancer patients who regularly took TAM were collected and the blood concentration of TAM and its metabolite Endoxifen was determined by HPLC-MS/MS and analyzed with nonlinear mixed-effect model (NONMEM). The population pharmacokinetics parameters were compared with those of volunteers in literatures. After that, 1 000 bootstraps were performed to validate the final model. RESULTS:A total of 29 patients took TAM. The mean age and BMI was (46.9±6.4) years and (23.70±2.87) kg/cm2, respectively. Typical population estimates of Ka, CLTAM, CLMET, VTAM, VEND, CLEND, Q were 0.830 h-1, 6.61 L/h, 0.707 L/h, 753 L, 400 L, 5.10 L/h, 61.8 L, respectively. Covariable screening showed OATP1B1*521 gene polymorphism and menopause time had an effect on metabolic constant CLTAM in the process of forward inclusion (P<0.05), but no significant covariable (P<0.001) was found in the process of backward elimination. The model validation of bootstraps results showed the success rate was 96.8%.CONCLUSION: The population pharmacokinetics model of TAM and END is established successfully. And it can provide some information for TAM clinical individualized medication from the perspective of pharmacometrics.

Key words: tamoxifen, breast cancer, population pharmacokinetics, OATP1B1

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