以基因导向为基础并分别使用NONMEM和Meta分析方法探讨苯妥英钠和华法林剂量个体化给药方案

发布时间：2018-06-27 01:23

本文选题：苯妥英钠 + 个体化给药　；参考：《安徽医科大学》2014年硕士论文

【摘要】：苯妥英钠（Phenytoin），又名苯妥英、大伦丁钠，是癫痫大发作时的首选药物。华法林（Warfarin）作为香豆素类口服抗凝药，目前广泛用于治疗心脏瓣膜置换术、深静脉血栓、肺栓塞、房颤等。这两种药物的治疗窗均较窄，血药浓度个体差异大，易受多种因素影响，因此对其实施个体化给药尤为必要。本研究分为以下两个部分：第一部分以基因导向和NONMEM为基础探讨苯妥英钠剂量个体化给药方案目的：以基因导向和NONMEM为基础，建立苯妥英钠群体药动学模型，优化初始给药剂量，进一步获得苯妥英钠剂量个体化给药方案，为临床合理使用苯妥英钠提供参考依据。方法：收集颅内肿瘤切除术后口服苯妥英钠以预防术后癫痫发作的112例病人的272个苯妥英钠血药浓度点和CYP2C9、CYP2C19基因分型及相关临床数据。应用非线性混合效应模型(nonlinear mixed effect model, NONMEM)软件求算药动学参数，建立基础模型和最终模型，并以最终模型设计其剂量个体化方案进行临床应用。结果：经NONMEM法对数据进行群体药动学分析，获得最终模型公式为：①CYP2C9*1/*1合并CYP2C19*1/*1或*1/*2或*1/*3时, Vmax=23.8×(WT/66.07)0.856×1.16(mg·h-1)，Km=5.84×0.731(mg·L-1)；②CYP2C9*1/*1合并CYP2C19*2/*2或*2/*3或*3/*3时，Vmax=23.8×(WT/66.07)0.856×0.874(mg·h-1)，Km=5.84×0.659(mg·L-1)；③CYP2C9*1/*3合并CYP2C19*1/*1或*1/*2或*1/*3或*2/*2或*2/*3或*3/*3时，Vmax=23.8×(WT/66.07)0.856×0.796(mg·h-1)，Km=5.84×0.291(mg·L-1)。采用Bootstrap法进行内部验证，，结果显示模型稳定、可靠。临床应用中，13例患者中有9例患者的苯妥英钠血药浓度在服药7天后达到有效治疗浓度水平（10~20mg·L-1）。结论：以基因导向和NONMEM为基础可获得颅内肿瘤切除术后患者体内苯妥英钠的群体药动学模型，内部验证结果显示该模型稳定可靠，可为临床设计苯妥英钠剂量个体化方案提供参考。第二部分以基因导向为基础，以meta分析法探讨华法林剂量的个体化给药方案目的：用meta分析方法探讨CYP2C9和VKORC1-1639GA不同基因型组合对华法林平均日剂量(Mean daily warfarin dose, MDWD)影响的定量关系，为临床设计华法林剂量个体化给药方案提供参考。方法：计算机检索相关期刊论文(CNKI)、中国生物医学文献数据库(CBM)、万方数据库、PubMed (2004.1~2013.7)，根据纳入标准对文献进行筛选和评估，采用RevMan5.1软件及Stata12.0软件对数据进行Meta分析。结果：共纳入包括998名患者在内的9篇研究，其中中文3篇，英文6篇。结果显示，与*1/*1+AA组相比，*1/*1+GG组、*1/*1+GA组和*1/*3+GA组MDWD分别升高1.01(95%CI:0.38,1.65, P=0.002)、0.41(95%CI:0.15,0.68, P=0.002)和0.06个标准单位(95%CI:－0.06,0.18, P=0.31)；*1/*3+AA组和*3/*3+AA组MDWD分别降低0.29(95%CI:－0.45,－0.13, P=0.0004)和0.38个标准单位(95%CI:－0.59,－0.17,P=0.0003)。敏感性分析表明，结果稳定。结论：本meta分析得到CYP2C9和VKORC1-1639GA不同基因型组合对华法林平均日剂量的影响的定量结果，该结果可对华法林个体化给药提供参考。
[Abstract]:In this study , it is especially necessary for the treatment of heart valve replacement , deep vein thrombosis , pulmonary embolism , atrial fibrillation , etc . The study is divided into two parts :

The first part , based on the genetic guidance and NONMEM , was used to study the dosage of sodium phentoylide .

Objective : To establish a pharmacokinetic model of phentolamine based on the genetic guidance and NONMEM , to optimize the initial dose of administration , to further obtain a dose - individualized dosing regimen of Phenylide , and to provide a reference for clinical rational use of sodium phentolamine .

Methods : 272 patients with epilepsy after resection of intracranial tumor were collected for prevention of post - operative epilepsy , and 272 patients with epilepsy were divided into two groups . The pharmacokinetic parameters were calculated by nonlinear mixed effect model ( NONMEM ) software , the basic model and the final model were established , and their dosage regimens were designed in the final model for clinical application .

RESULTS : The data were analyzed by NONMEM method . The formula of the final model was as follows : ( 1 ) Vmax = 23.8 脳 ( WT / 66.07 ) 0.856 脳 1.16 ( mg 路 h - 1 ) , Km = 5.84 脳 0.731 ( mg 路 L - 1 ) .
( 2 ) Vmax = 23 . 8 脳 ( WT / 66.07 ) 0.856 脳 0.874 ( mg 路 h - 1 ) , Km = 5.84 脳 0.659 ( mg 路 L - 1 ) ;
In clinical application , 9 out of 13 patients received effective treatment concentration ( 10 ~ 20mg 路 L - 1 ) after 7 days of administration .

Conclusion : Based on the gene guidance and NONMEM , the pharmacokinetic model of phentolamine in patients with intracranial tumor resection is obtained . The results of internal verification show that the model is stable and reliable , which can provide a reference for clinical design of sodium phentolamine dosage regimens .

The second part is based on gene guidance , and the individual dosage regimen of warfarin dosage is discussed by meta - analysis .

Objective : To study the quantitative relationship between the effects of different genotype combinations on mean daily warfarin dose ( MDWD ) and mean daily warfarin dose ( MDWD ) by meta - analysis .

Methods : The Chinese Journal Full - Text Database ( CNKI ) , Chinese Biomedical Literature Database ( CBM ) , Wanfang Database ( 2004 . 1 - 2013 . 7 ) were searched and the literature was screened and evaluated according to the inclusion criteria , and the data were analyzed by RevMan5.1 software and Stata12.0 software .

Results : Nine studies including 998 patients were included , including 3 Chinese and 6 in English . Results showed that MDWD increased 1.01 ( 95 % CI : 0.38 , 1.65 , P = 0.002 ) , 0.41 ( 95 % CI : 0.15 , 0.68 , P = 0.002 ) and 0.06 standard units ( 95 % CI : - 0.06 , 0.18 , P = 0.31 ) compared with the * 1 / * 1 + AA group .
* 1 / * 3 + AA group and * 3 / * 3 + AA group MDWD decreased 0.29 ( 95 % CI : - 0.45 , - 0.13 , P = 0.0004 ) and 0.38 standard units ( 95 % CI : - 0.59 , - 0.17 , P = 0.0003 ) , respectively . The sensitivity analysis shows that the results are stable .

Conclusion : This meta - analysis results in the quantitative results of the effects of different genotypes on the mean daily dose of warfarin . The results can provide reference for individual administration of warfarin .
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R969.1

【参考文献】