基于群体药代动力学研究的奥氮平PK参数分析

doi:10.3969/j.issn.1000-8535.2024.06.007

摘要/Abstract

摘要： 目的通过分析奥氮平的群体药代动力学研究,探讨影响奥氮平药动学参数的因素,为临床制定个体化给药方案提供依据。方法在中国知网、万方、维普、迈特思创、PubMed和Embase等中英文数据库,以“奥氮平”“群体药代动力学”“模型”“非线性混合效应模型”及“olanzapine pamoate”“olanzapine”“population pharmacokinetic”“pharmacokinetic model”“nonlinear mixed effect”“NONMEM”为检索策略,检索建库至2023年5月所有关于奥氮平群体药代动力学的研究。结果共纳入14篇奥氮平的群体药代动力学研究,大多数研究将奥氮平的药代动力学描述为一个单室模型。成人群体药代动力学模型群体典型值吸收速率常数：（0.3~2.85）/h;表观分布清除率：（10.4~25.4）L/h;表观分布容积：（223~2 390）L。儿童青少年模型群体典型值吸收速率常数：（0.142~0.758）/h;表观分布清除率：（13.6~16.8）L/h;表观分布容积：（322~899）L。年龄、体质量、性别、种族、吸烟状况、合并用药是影响奥氮平药动学参数的显著协变量。结论奥氮平药动学参数估计值存在差异且有不同程度的个体间变异,未来应侧重于对特殊人群的研究。有必要对先前发表的模型进行外部验证,以便更准地的描述模型的适用性。

关键词: 奥氮平, 群体药代动力学, 非线性混合效应模型, 个体化给药

Abstract: Objective By analyzing the population pharmacokinetics of olanzapine,the factors affecting the pharmacokinetic parameters of olanzapine were discussed,so as to provide a basis for the clinical formulation of individualized dosing regimens．Methods In Chinese and English databases such as CNKI,Wanfang,Wipro database,FMRS,PubMed and Embase,all studies on population pharmacokinetics of olanzapine from the establishment of the database to May 2023 were searched with “olanzapine pamoate”“olanzapine”,“population pharmacokinetics”,“pharmacokinetic model”,“nonlinear mixed-effect” and “NONMEM” as key words．Results A total of 14 population pharmacokinetic studies of olanzapine were included．Most studies described the pharmacokinetics of olanzapine as a single-chamber model．Adult pharmacokinetic model population typical values absorption rate constant was（0.3-2.85）/h;apparent distribution clearance was（10.4-25.4）L/h;apparent volume of distribution was（223-2390）L．absorption rate constants of the population of children and adolescents was（0.142-0.758）/h,apparent distribution clearance was（13.6-16.8）L/h,apparent volume of distribution was（322-899）L．Age,weight,gender,ethnicity,smoking status and concomitant medication were significant covariates affecting the pharmacokinetic parameters of olanzapine．Conclusions Estimates of pharmacokinetic parameters of olanzapine vary and have varying degrees of inter-individual variation．In the future,research should focus on special populations．Externally validation of previously published models should also be performed to more accurately describe the applicability of the models．

Key words: olanzapine, population pharmacokinetics, nonlinear mixed-effects model, individualized dosing

李思民, 孙红梅, 吴丹, 聂彩霞, 陈路琼. 基于群体药代动力学研究的奥氮平PK参数分析[J]. 广州医药, 2024, 55(6): 618-625.

LI Simin, SUN Hongmei, WU Dan, NIE Caixia, CHEN Luqiong. Analysis of olanzapine PK parameters based on population pharmacokinetic studies[J]. Guangzhou Medical Journal, 2024, 55(6): 618-625.

参考文献

[1] SORIA-CHACARTEGUI P,VILLAPALOS-GARCIA G,ZUBIAUR P,et al.Genetic polymorphisms associated with the pharmacokinetics,pharmacodynamics and adverse effects of olanzapine,aripiprazole and risperidone[J].Front Pharmacol,2021(12):711940.
[2] 刘昀,古美玲,庄淑丽.基于中国PIM标准分析老年精神疾病住院患者潜在不适当用药现状[J].广州医药,2022,53(3):57-61.
[3] KOLLER D,ALMENARA S,MEJÍA G,et al.Metabolic effects of aripiprazole and olanzapine multiple-dose treatment in a randomised crossover clinical trial in healthy volunteers:Association with pharmacogenetics[J].Adv Ther,2021,38(2):1035-1054.
[4] MOSCHNY N,HEFNER G,GROHMANN R,et al.Therapeutic drug monitoring of second-and third-generation antipsychotic drugs-influence of smoking behavior and inflammation on pharmacokinetics[J].Pharmaceuticals(Basel),2021,14(6):514.
[5] HIEMKE C,BERGEMANN N,CLEMENT H W,et al.Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology:Update 2017[J].Pharmacopsychiatry,2018,51(1-2):e1.
[6] MAHARAJ A R,WU H,ZIMMERMAN K O,et al.Population pharmacokinetics of olanzapine in children[J].Br J Clin Pharmacol,2021,87(2):542-554.
[7] LI A,JI S,YUE W,et al.Development of a population pharmacokinetic model of olanzapine for Chinese health volunteers and patients with schizophrenia[J].BMJ Open,2018,8(8):e020070.
[8] SUN L,MILLS R,SADLER B M,et al.Population pharmacokinetics of olanzapine and samidorphan when administered in combination in healthy subjects and patients with schizophrenia[J].J Clin Pharmacol,2021,61(11):1430-1441.
[9] XIAO T,HU J Q,LIU S J,et al.Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients:Based on the impact of sex and concomitant valproate on clearance[J].J Clin Pharm Ther,2022,47(11):1811-1819.
[10] LOBO E D,ROBERTSON-PLOUCH C,QUINLAN T,et al.Oral olanzapine disposition in adolescents with schizophrenia or bipolar I disorder:A population pharmacokinetic model[J].Paediatr Drugs,2010,12(3):201-211.
[11] DAVIES S J,MULSANT B H,FLINT A J,et al.The impact of sertraline co-administration on the pharmacokinetics of olanzapine:A population pharmacokinetic analysis of the STOP-PD[J].Clin Pharmacokinet,2015,54(11):1161-1168.
[12] ZANG Y N,DONG F,LI A N,et al.The impact of smoking,sex,infection,and comedication administration on oral olanzapine:A population pharmacokinetic model in Chinese psychiatric patients[J].Eur J Drug Metab Pharmacokinet,2021,46(3):353-371.
[13] YIN A,SHANG D,WEN Y,et al.Population pharmacokinetics analysis of olanzapine for Chinese psychotic patients based on clinical therapeutic drug monitoring data with assistance of meta-analysis[J].Eur J Clin Pharmacol,2016,72(8):933-944.
[14] 杜萍,李鹏飞,刘洪川,等.奥氮平在中国健康人体中群体药代动力学研究[J].中国临床药理学杂志,2019,35(15):1652-1656.
[15] XIAO T,WANG Z,LI G,et al.What to do about missed doses? A retrospective study of olanzapine in the elderly[J].Drug Des Devel Ther,2021(15):3411-3423.
[16] BIGOS K L,POLLOCK B G,COLEY K C,et al.Sex,race,and smoking impact olanzapine exposure[J].J Clin Pharmacol,2008,48(2):157-165.
[17] WANG X,HAN Y,ZHOU H,et al.Prediction of steady-state plasma concentrations of olanzapine in Chinese Han in patients based on a retrospective population pharmacokinetic model[J].2021,20(11):2433-2441.
[18] PILLA R V,KOZIELSKA M,SULEIMAN A A,et al.Pharmacokinetic-pharmacodynamic modeling of antipsychotic drugs in patients with schizophrenia Part I:The use of PANSS total score and clinical utility[J].Schizophr Res,2013,146(1-3):144-152.
[19] CATAFAU A M,PENENGO M M,NUCCI G,et al.Pharmacokinetics and time-course of D(2)receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients[J].J Psychopharmacol,2008,22(8):882-894.
[20] 肖桃. 基于群体药代动力学建模与仿真技术实施奥氮平在特殊人群的个体化用药研究[D].广州:广州医科大学,2022.
[21] DENG S H,WANG Z Z,LU H Y,et al.A retrospective analysis of steady-state olanzapine concentrations in Chinese patients using therapeutic drug monitoring:Effects of valproate and other factors[J].Ther Drug Monit,2020,42(4):636-642.
[22] 闫盼,宋明芬,王晟东,等.CYP1A2基因多态性对精神分裂症患者奥氮平血药浓度的影响[J].中华全科医学,2020,18(11):1851-1853,1939.
[23] 张巧真,黄敏芳,宋伟明.4969例奥氮平血药浓度日常检测及药师干预分析[J].现代实用医学,2018,30(4):492-493.
[24] DING J,ZHANG Y,ZHANG Y,et al.Effects of age,sex,and comedication on the plasma concentrations of olanzapine in Chinese patients with schizophrenia based on therapeutic drug monitoring data[J].J Clin Psychopharmacol,2022,42(6):552-559.
[25] TSIOKOU V,KILINDRIS T,BEGAS E,et al.Altered activity of xenobiotic detoxifying enzymes at menopause-A cross-sectional study[J].Environ Res,2020(182):109074.
[26] 钟璐莲,陈政,彭陈陈,等.阿立哌唑血药浓度/剂量比影响因素分析及临床应用[J].广州医药,2022,53(3):100-103.
[27] PATEL M X,BOWSKILL S,COUCHMAN L,et al.Plasma olanzapine in relation to prescribed dose and other factors:Data from a therapeutic drug monitoring service,1999-2009[J].J Clin Psychopharmacol,2011,31(4):411-417.
[28] AN H,FAN H,CHEN S,et al.Effects of dose,age,sex,body weight,and smoking on plasma concentrations of olanzapine and N-desmethyl olanzapine in inpatients with schizophrenia[J].J Clin Psychopharmacol,2021,41(3):255-259.
[29] SUN L,YAGODA S,DU Y,et al.Effect of hepatic and renal impairment on the pharmacokinetics of olanzapine and samidorphan given in combination as a bilayer tablet[J].Drug Des Devel Ther,2019(13):2941-2955.
[30] CITROME L,STAUFFER V L,CHEN L,et al.Olanzapine plasma concentrations after treatment with 10,20,and 40 mg/d in patients with schizophrenia:An analysis of correlations with efficacy,weight gain,and prolactin concentration[J].J Clin Psychopharmacol,2009,29(3):278-283.
[31] ROJAS-MACETAS A,MEDALLA-GARRO G,SARAVIA M,et al.Potential polymorphic CYP1A2 and CYP2D6-mediated pharmacokinetic interactions between risperidone or olanzapine and selected drugs intended to treat COVID-19[J].Drug Metab Bioanal Lett,2022.
[32] FEKETE F,MENUS Á,TÓTH K,et al.CYP1A2 expression rather than genotype is associated with olanzapine concentration in psychiatric patients[J].Sci Rep,2023,13(1):18507.
[33] DJORDJEVIC N,RADMANOVIC B,CUKIC J,et al.Cigarette smoking and heavy coffee consumption affecting response to olanzapine:The role of genetic polymorphism[J].World J Biol Psychiatry,2020,21(1):29-52.
[34] 张冬阳,宋明芬,闫盼,等.氟伏沙明和CYP1A2~*1F基因多态性对血清奥氮平浓度的影响[J].中国现代应用药学,2020,37(5):591-594.
[35] 胡晋卿,肖桃,朱秀清,等.奥氮平联合舍曲林对于奥氮平血药浓度的影响研究[J].中国医院用药评价与分析,2023,23(3):264-267.