本文選題：群體藥代動(dòng)力學(xué) + NONMEM��； 參考：《皖南醫(yī)學(xué)院》2017年碩士論文

【摘要】：目的:采用群體藥代動(dòng)力學(xué)的方法,建立他莫昔芬(Tamoxifen,TAM)及主要活性代謝產(chǎn)物Endoxifen在乳腺癌患者體內(nèi)的群體藥代動(dòng)力學(xué)模型,探討代謝酶和轉(zhuǎn)運(yùn)體的基因多態(tài)性對(duì)TAM和Endoxifen在乳腺癌患者體內(nèi)藥代動(dòng)力學(xué)特征的影響。方法:1)建立高效液相色譜-串聯(lián)質(zhì)譜(High performance liquid chromatography-tandem mass spectrometry,HPLC-MS/MS)檢測(cè)人全血中TAM及其代謝產(chǎn)物Endoxifen的定量分析方法,驗(yàn)證該方法的專屬性、穩(wěn)定性、精密度和回收率等。2)收集自2009年長(zhǎng)期服用TAM的女性乳腺癌患者病例,經(jīng)知情同意后采集血液樣本,搜集人口學(xué)信息(年齡、身高、體重、BMI等),及臨床信息(持續(xù)服用TAM時(shí)間、患病時(shí)間等),測(cè)定所采集樣本中TAM和Endoxifen的血藥濃度,并檢測(cè)所有受試患者CYP2C19*2、CYP2C19*3、OATP1B1*388和OATP1B1*521的基因多態(tài)性。3)將測(cè)得受試患者體內(nèi)TAM和Endoxifen的血藥濃度數(shù)據(jù),結(jié)合對(duì)應(yīng)患者的基本人口學(xué)信息、臨床信息和基因分型等協(xié)變量,最終通過(guò)NONMEM軟件構(gòu)建TAM在乳腺癌患者體內(nèi)的群體藥代動(dòng)力學(xué)模型。結(jié)果:1)本研究中建立了HPLC-MS/MS定量檢測(cè)人全血中TAM及Endoxifen濃度的分析方法專屬性和靈敏度均符合要求。2)本研究共收集了29例長(zhǎng)期服用TAM的乳腺癌患者,其中2例未提供人口學(xué)信息,5例患者在樣本采集后期存在合并用藥現(xiàn)象,剩余22例患者中,平均年齡為46.9±6.4歲,平均身高為1.60±0.04m,平均體重為60.9±8.1kg,平均BMI值為23.70±2.87,絕經(jīng)者15例,未絕經(jīng)者7例,平均絕經(jīng)時(shí)間為43.7±66.6月�；蛐蜏y(cè)定結(jié)果顯示,除OATP1B1*388具有雙位點(diǎn)突變外,OATP1B1*521、CYP2C19*2、CYP2C19*3等位點(diǎn)均只存在單位點(diǎn)突變。其中,CYP2C19*2未突變基因型有13例,單位點(diǎn)突變基因型有9例;CYP2C19*3未突變基因型有16例,單位點(diǎn)突變基因型有6例;OATP1B1*388未突變基因型有1例,單位點(diǎn)突變基因型有6例,雙位點(diǎn)突變基因型有15例;OATP1B1*521未突變基因型有14例,單位點(diǎn)突變基因型有8例。3)模型中TAM和Endoxifen的個(gè)體預(yù)測(cè)值與實(shí)測(cè)值相關(guān)性良好,而且群體預(yù)測(cè)濃度和標(biāo)本采集時(shí)間與條件權(quán)重殘差(CWRES)之間無(wú)明顯偏倚,多數(shù)濃度的預(yù)測(cè)差在2倍標(biāo)準(zhǔn)偏差(SD)之內(nèi),證明基礎(chǔ)模型預(yù)測(cè)效果良好。通過(guò)向前包容法發(fā)現(xiàn),在TAM的群體藥代動(dòng)力學(xué)模型中,除了OATP1B1*521的基因多態(tài)性和絕經(jīng)時(shí)間對(duì)TAM的代謝系數(shù)CLTAM有顯著性統(tǒng)計(jì)學(xué)影響外(P0.05),在模型中添加CYP2C19*2、CYP2C19*3、OATP1B1*388的基因多態(tài)性以及其他協(xié)變量對(duì)任何參數(shù)均無(wú)顯著性統(tǒng)計(jì)學(xué)差異(P0.05)。結(jié)論:1)本研究中建立的HPLC-MS/MS檢測(cè)人血液中TAM及Endoxifen濃度的定量分析方法專屬性和靈敏度均符合要求,測(cè)定結(jié)果準(zhǔn)確、穩(wěn)定。2)本研究成功的構(gòu)建了TAM在乳腺癌患者體內(nèi)的群體藥代動(dòng)力學(xué)模型,模型的診斷結(jié)果良好。協(xié)變量的考察結(jié)果顯示,OATP1B1*521位點(diǎn)的基因多態(tài)性和絕經(jīng)時(shí)間可能影響了TAM在乳腺癌患者體內(nèi)的藥代動(dòng)力學(xué)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 鹵6.4 years, the average height was 1.60 鹵0.04m, the average body weight was 60.9 鹵8.1 kg, the average BMI value was 23.70 鹵2.87, and 15 cases were menopausal. The mean menopausal time was 43.7 鹵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.
【學(xué)位授予單位】：皖南醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R969.1

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