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/cm^2。最终模型的药代动力学参数估计值分别为,K_a为0.830 h^(-1);CL_(TAM)为6.61 L/h;CL_(MET)为0.707 L/h;V_(TAM)为753 L;V_(END)为400 L;CL_(END)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CL_(TAM)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。
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/cm^2, respectively. Typical population estimates of K a, CL TAM , CL MET , V TAM , V END , CL END , 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 CL TAM 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.
作者
吴敏
过怿赟
谢海棠
WU Min;GUO Yiyun;XIE Haitang(Department of Drug and Consumable Supply,the Second People's Hospital of Wuhu,Wuhu 241001,Anhui,China;Department of Clinical Pharmacy,Yijishan Hospital of Wannan Medical College,Wuhu 241001,Anhui,China)
出处
《中国临床药理学与治疗学》
CAS
CSCD
2019年第4期418-423,共6页
Chinese Journal of Clinical Pharmacology and Therapeutics
基金
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)
