他莫昔芬在乳腺癌患者体内的群体药代动力学研究

发布时间：2018-05-07 22:18

本文选题：群体药代动力学 + NONMEM　；参考：《皖南医学院》2017年硕士论文

【摘要】：目的:采用群体药代动力学的方法,建立他莫昔芬(Tamoxifen,TAM)及主要活性代谢产物Endoxifen在乳腺癌患者体内的群体药代动力学模型,探讨代谢酶和转运体的基因多态性对TAM和Endoxifen在乳腺癌患者体内药代动力学特征的影响。方法:1)建立高效液相色谱-串联质谱(High performance liquid chromatography-tandem mass spectrometry,HPLC-MS/MS)检测人全血中TAM及其代谢产物Endoxifen的定量分析方法,验证该方法的专属性、稳定性、精密度和回收率等。2)收集自2009年长期服用TAM的女性乳腺癌患者病例,经知情同意后采集血液样本,搜集人口学信息(年龄、身高、体重、BMI等),及临床信息(持续服用TAM时间、患病时间等),测定所采集样本中TAM和Endoxifen的血药浓度,并检测所有受试患者CYP2C19*2、CYP2C19*3、OATP1B1*388和OATP1B1*521的基因多态性。3)将测得受试患者体内TAM和Endoxifen的血药浓度数据,结合对应患者的基本人口学信息、临床信息和基因分型等协变量,最终通过NONMEM软件构建TAM在乳腺癌患者体内的群体药代动力学模型。结果:1)本研究中建立了HPLC-MS/MS定量检测人全血中TAM及Endoxifen浓度的分析方法专属性和灵敏度均符合要求。2)本研究共收集了29例长期服用TAM的乳腺癌患者,其中2例未提供人口学信息,5例患者在样本采集后期存在合并用药现象,剩余22例患者中,平均年龄为46.9±6.4岁,平均身高为1.60±0.04m,平均体重为60.9±8.1kg,平均BMI值为23.70±2.87,绝经者15例,未绝经者7例,平均绝经时间为43.7±66.6月。基因型测定结果显示,除OATP1B1*388具有双位点突变外,OATP1B1*521、CYP2C19*2、CYP2C19*3等位点均只存在单位点突变。其中,CYP2C19*2未突变基因型有13例,单位点突变基因型有9例;CYP2C19*3未突变基因型有16例,单位点突变基因型有6例;OATP1B1*388未突变基因型有1例,单位点突变基因型有6例,双位点突变基因型有15例;OATP1B1*521未突变基因型有14例,单位点突变基因型有8例。3)模型中TAM和Endoxifen的个体预测值与实测值相关性良好,而且群体预测浓度和标本采集时间与条件权重残差(CWRES)之间无明显偏倚,多数浓度的预测差在2倍标准偏差(SD)之内,证明基础模型预测效果良好。通过向前包容法发现,在TAM的群体药代动力学模型中,除了OATP1B1*521的基因多态性和绝经时间对TAM的代谢系数CLTAM有显著性统计学影响外(P0.05),在模型中添加CYP2C19*2、CYP2C19*3、OATP1B1*388的基因多态性以及其他协变量对任何参数均无显著性统计学差异(P0.05)。结论:1)本研究中建立的HPLC-MS/MS检测人血液中TAM及Endoxifen浓度的定量分析方法专属性和灵敏度均符合要求,测定结果准确、稳定。2)本研究成功的构建了TAM在乳腺癌患者体内的群体药代动力学模型,模型的诊断结果良好。协变量的考察结果显示,OATP1B1*521位点的基因多态性和绝经时间可能影响了TAM在乳腺癌患者体内的药代动力学特性。
[Abstract]:Objective: to establish a population pharmacokinetic model of tamoxifenol (Tamoxifentam) and its main metabolite Endoxifen in breast cancer patients by the method of population pharmacokinetics. To investigate the effect of gene polymorphisms of metabolic enzymes and transporters on the pharmacokinetics of TAM and Endoxifen in breast cancer patients. Methods: to establish a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) method for the determination of TAM and its metabolite Endoxifen in human whole blood, and to verify the specificity and stability of the method. Blood samples were collected from female breast cancer patients who had taken TAM for a long time in 2009. Demographic information (age, height, weight, etc.) and clinical information (duration of continuous use of TAM) were collected. The blood drug concentrations of TAM and Endoxifen in the samples were measured, and the gene polymorphisms of CYP2C19C19C192CYP2C191B1B1C388 and OATP1B1*521 were detected in all patients. The data of serum drug concentrations of TAM and Endoxifen in the patients were measured, and combined with the basic demographic information of the corresponding patients. Finally, the pharmacokinetic model of TAM in breast cancer patients was constructed by NONMEM software and covariates such as clinical information and genotyping. Results the specificity and sensitivity of HPLC-MS/MS for quantitative determination of TAM and Endoxifen in human whole blood were established. 2) 29 breast cancer patients who took TAM for a long time were collected in this study. Of the 22 patients, the average age was 46.9 卤6.4 years, the average height was 1.60 卤0.04m, the average body weight was 60.9 卤8.1 kg, the average BMI value was 23.70 卤2.87, and 15 cases were menopausal. The mean menopausal time was 43.7 卤66.6 months. The results of genotypic analysis showed that there was only a unit point mutation at all sites except OATP1B1*388 with double locus mutation in OATP-1B1B1C521, CYP2C19, CYP2C19 and CYP2C19O3. There were 13 unmutated genotypes of CYP2C19k2, 9 cases of unmutated genotypes of CYP2C19C19k3, 6 cases of unmutation genotypes of unit point mutation genotypes, and 6 cases of unmutated genotypes of unit point mutations. The individual predictive values of TAM and Endoxifen were correlated well with the measured values in 15 cases of double locus mutation genotypes and 14 cases of non-mutation genotypes of OATP 1B1C521 and 8 cases of unit point mutation genotypes. Moreover, there is no obvious bias between population prediction concentration and sample collection time and conditional weight residuals. The prediction difference of most concentrations is within 2 times standard deviation (SDSD), which proves that the prediction effect of the basic model is good. In the population pharmacokinetic model of TAM, we found that, Except that the polymorphism of OATP1B1*521 gene and menopause time had significant statistical influence on the metabolic coefficient of TAM (CLTAM), there was no significant statistical difference in the gene polymorphism of CYP2C19C192C2C192C192CYP2C193OATPase 1B1h388 and other covariables to any parameter (P0.05). Conclusion (1) the specificity and sensitivity of the HPLC-MS/MS method established in this study for the determination of TAM and Endoxifen in human blood are in accordance with the requirements, and the results are accurate. The pharmacokinetic model of TAM in breast cancer patients was successfully constructed, and the diagnostic results of the model were satisfactory. The results of covariate analysis showed that the gene polymorphism and menopausal time of OATP 1B1N 521 might affect the pharmacokinetic characteristics of TAM in breast cancer patients.
【学位授予单位】：皖南医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R969.1

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