伊潘立酮片在中国健康志愿者及精神分裂症患者中的药动学研究

发布时间：2018-04-26 01:37

本文选题：伊潘立酮 + 药动学　；参考：《中南大学》2014年硕士论文

【摘要】：一、目的 (1)研究伊潘立酮及代谢产物在中国健康志愿者中的药动学特征； (2)建立伊潘立酮干预精神分裂症病患者群体药动学模型,获得群体药动学参数,评价群体参数的影响因素； (3)研究CYP2D6*10(rs1065852)基因型对伊潘立酮及代谢产物血药浓度和药动学参数的影响。二、方法 (1)按入选／排除标准筛选中国健康志愿者16例,进行随机、开放、两剂量(lmg、3mg)、双周期叉试验。洗脱期14天。采取给药前及给药后0.5、1、1.5、2、3、4、6、8、12、24、36、48、72、96和120h系列血样,HPLC-MS/MS法测定伊潘立酮及代谢产物(M1,M2)血药浓度,WinNolin软件计算药动学参数,SPSS18.0软件进行统计分析。 (2)按入选/排标准筛选精神分裂症患者70例,收集基本信息；采集连续给药(剂量滴定后)第15天,第28天谷浓度及第28天给药后4、12h血样;HPLC-MS/MS法测定伊潘立酮及代谢产物(M1,M2)血药浓度；SPSS18.0对数据进行统计分析,NONMEM软件建立群体药动学模型。 (3)收集完成药动学研究健康志愿者(14名)和精神分裂症患者(70名)血液样本,提取外周淋巴细胞DNA,基因测序法对CYP2D6*10(rs1065852)进行基因分型,SPSS18.0对基因型与血药浓度、药动学参数进行相关性分析。三、结果 (1)口服伊潘立酮片后,伊潘立酮、M1符合二室模型,M2符合一室模型。伊潘立酮主要药动学参数Cmax、AUC、CL/F在剂量间、个体间差异有统计学意义；伊潘立酮的AUC和Cmax的增加不呈剂量比例关系；健康志愿者服用伊潘立酮片后不良反应发生率高。 (2)群体药动学模型显示,引入变量可部分解释个体间差异：CYP2D6*10突变影响伊潘立酮经其他途径消除速率常数(K20)和M2生成速率(K24),K20和K24个体间差异分别下降1.8%和7%；红细胞数(RBC)引入模型后,伊潘立酮分布容积V2的个体差异下降1.3%。 (3)健康志愿者和精神分裂症患者中CYP2D6*10基因型频率分别为21.4%和24.3%；精神分裂症患者中CYP2D6*10TT携带者伊潘立酮和M1浓度／剂量校正值升高,而M2的校正值降低；健康志愿者CYP2D6*10基因型组间药动学参数差异无统计学意义。四、结论 (1)单次口服lmg和3mg剂量时,伊潘立酮在中国健康志愿者中药动学参数增加与剂量不呈比例关系,部分药动学参数高于国外报道,耐受剂量低,不良反应发生率高。 (2)本研究建立的伊潘立酮群体药动学模型显示CYP2D6*10突变和红细胞数可降低群体参数K20、K24和V2的个体间变异,能部分解释伊潘立酮清除和分布的个体间变异。 (3)CYP2D6*10(rs1065852)基因型影响伊潘立酮干预精神分裂症患者伊潘立酮和代谢产物的稳态血药浓度。
[Abstract]:I. purpose 1) to study the pharmacokinetic characteristics of ipyridone and its metabolites in Chinese healthy volunteers. (2) to establish a group pharmacokinetic model of patients with schizophrenia treated with Ipperidone, to obtain the population pharmacokinetic parameters and to evaluate the influencing factors of the population parameters. To study the effect of CYP2D6 (10rs1065852) genotype on the plasma concentration and pharmacokinetic parameters of iperidone and its metabolites. II. Methodology 1) Sixteen Chinese healthy volunteers were selected according to the criteria of inclusion / exclusion, randomized, open, two doses of LMG 3 mg / g, double cycle fork test. The elution period is 14 days. The pharmacokinetic parameters were calculated by WinNolin software (SPSS 18.0) before and after the administration of the drug. The pharmacokinetic parameters were calculated by the software WinNolin, which was used to calculate the pharmacokinetic parameters of Ipperidone and its metabolite M _ (1) M _ (2) by the method of HPLC-MSMS for the determination of Ipantone and its metabolite M _ (1) / M _ (2) before and after the administration of the drug. The results were analyzed by SPSS 18.0 software. The pharmacokinetic parameters were analyzed by SPSS 18.0 software. (2) 70 schizophrenic patients were screened according to the inclusion / row criteria, and basic information was collected, and the 15th day after continuous administration (dose titration) was collected. The serum concentrations of Ipperidone and its metabolite were determined by HPLC-MS / MS method on the 28th day and 42 h after administration. SPSS 18.0 was used to analyze the data and to establish a colony pharmacokinetic model by NONMEM software. Blood samples were collected from 14 healthy volunteers and 70 schizophrenic patients. Peripheral lymphocyte DNA was extracted. The genotypes of CYP2D6 and 10rs1065852) were genotyped by SPSS 18.0 pairs. Correlation analysis of pharmacokinetic parameters was carried out. III. Results 1) after oral administration of Ipperidone tablets, the two compartment model (M 2) and the one compartment model (M 2) of Ipperidone M 1 were conformed to the two compartment model. The main pharmacokinetic parameters of Ipperidone were C _ max AUC _ (C) C / F, there was significant difference among individuals, the increase of AUC and Cmax was not dose-proportional, and the incidence of adverse reactions was higher in healthy volunteers after taking Ipperidone tablets. 2) the population pharmacokinetic model showed that, The introduction of variables can partly explain the effect of the mutation of different individuals: CYP2D6N10 on the elimination of rate constant K20) and the rate of M2 production by 1.8% and 7%, respectively, and the RBCs of erythrocyte number were introduced into the model. The individual difference in the volume V _ 2 of the distribution of Ipperidone decreased by 1.3%. (3) the frequency of CYP2D6*10 genotype in healthy volunteers and schizophrenia patients was 21.4% and 24.30.The corrected values of Ipperidone and M1 concentration / dose of CYP2D6*10TT carriers in schizophrenic patients were increased, but the corrected values of M2 were decreased. There was no significant difference in pharmacokinetic parameters among CYP2D6*10 genotypes in healthy volunteers. IV. Conclusions 1) the increase of pharmacokinetic parameters was not proportional to the dose of lmg and 3mg in Chinese healthy volunteers. Some pharmacokinetic parameters were higher than those reported abroad, the tolerance dose was low, and the incidence of adverse reactions was high. 2) the population pharmacokinetic model established in this study showed that CYP2D6*10 mutation and erythrocyte number could decrease the inter-individual variation of population parameters K20K24 and V2, and could partly explain the inter-individual variation of the clearance and distribution of Ipperidone. The genotype of CYP2D6 (10rs1065852) affects the steady-state plasma concentrations of Ipperidone and its metabolites in patients with schizophrenia.
【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R969

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