乳腺癌患者体内他莫昔芬的群体药代动力学研究

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。

Population pharmacokinetics of tamoxifen in patients with breast cancer

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.