群体药物动力学分析软件的应用研究与技术开发
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摘要
群体药物动力学是研究药物在某一特定群体中的动力学特征,通过统计学处理来全面分析药物与机体的各种相互作用。它强有力的分析能力可以揭示药物在进入体内后与机体之间较深层次的各种相互关系,所以得到了人们越来越多的重视,在药物的基础研究以及临床应用方面均有较广阔的前景。
本文首先阐述了药物动力学以及群体药物动力学的基础知识以及相关参数的求算方法,而后重点研究了药物动力学及群体药物动力学的基本研究方法,尤其是其中应用最为广泛的非线性混合效应模型法(NONMEM)。研究了根据此法编制而成的现在应用最广泛也是主要流行的群体药物动力学软件NONMEM,以研究NONMEM采用了扩展最小二乘法的核心算法为主,通过比较几种不同的方法,指出了几种算法所存在的不足,并且提出了使用改进的非线性单纯形法的算法,并进行了验证。
本文进行了如下工作:
(1)阐述了群体药物动力学研究的意义所在,对相关概念及知识做了较为详尽的阐述,并且分析了目前国内外相关研究发展状况。
(2)对NONMEM软件做了重点研究,针对其算法提出了使用改进的非线性单纯形法来进行数据拟合,通过将问题转化为求最优解而减少相关计算量,增加计算精度。
(3)对现有的非线性单纯形法做了一定的改进,增加了新的判断方向,对单纯形的扩展部分做了进一步的改进,使得最终单纯形尽可能保证不出现退化。
Population pharmacokinetics studied dynamic characteristics of drugs in a particular group, adopted a comprehensive statistical analysis of drug treatment to a variety of interactions with the body. It can be a powerful analytical capability revealed the deeper level of mutual relations between the body and drugs after drugs entering the body. There is growing attention to it, and it has shown broad prospects in the basis of drug research and clinical applications.
This paper introduces the basis knowledge of pharmacokinetics and population pharmacokinetics, the relevant parameters for calculating method, and focused on the pharmacokinetics and population pharmacokinetics basic research methods, especially the nonlinear mixed effect method (NONMEM) which the most widely used method. This paper studies the core algorithm of NONMEM that based extended least squares. It points out the insufficiency of the several algorithms by comparing several different methods, and a new algorithm that based on improved nonlinear simplex method was proposed and was verified.
This paper carries on the following works:
(1) It shows the significance of the research of the population pharmacokinetics, shows the related concepts and knowledge in detail, and analyses the research and development status about population pharmacokinetics at home and abroad at present.
(2) Research-emphasis is the algorithm of NONMEM. The core fitting algorithm of NONMEM was studied and improved through the use of improved nonlinear simplex method, and reduces the amount of computation through conversion issues for the sake of the optimal solution.
(3) Improve the existing algorithms through add a new judgment direction, and improve the extension part of the nonlinear simplex method, and ensure that there is no degradation about the final simplex.
本文首先阐述了药物动力学以及群体药物动力学的基础知识以及相关参数的求算方法,而后重点研究了药物动力学及群体药物动力学的基本研究方法,尤其是其中应用最为广泛的非线性混合效应模型法(NONMEM)。研究了根据此法编制而成的现在应用最广泛也是主要流行的群体药物动力学软件NONMEM,以研究NONMEM采用了扩展最小二乘法的核心算法为主,通过比较几种不同的方法,指出了几种算法所存在的不足,并且提出了使用改进的非线性单纯形法的算法,并进行了验证。
本文进行了如下工作:
(1)阐述了群体药物动力学研究的意义所在,对相关概念及知识做了较为详尽的阐述,并且分析了目前国内外相关研究发展状况。
(2)对NONMEM软件做了重点研究,针对其算法提出了使用改进的非线性单纯形法来进行数据拟合,通过将问题转化为求最优解而减少相关计算量,增加计算精度。
(3)对现有的非线性单纯形法做了一定的改进,增加了新的判断方向,对单纯形的扩展部分做了进一步的改进,使得最终单纯形尽可能保证不出现退化。
Population pharmacokinetics studied dynamic characteristics of drugs in a particular group, adopted a comprehensive statistical analysis of drug treatment to a variety of interactions with the body. It can be a powerful analytical capability revealed the deeper level of mutual relations between the body and drugs after drugs entering the body. There is growing attention to it, and it has shown broad prospects in the basis of drug research and clinical applications.
This paper introduces the basis knowledge of pharmacokinetics and population pharmacokinetics, the relevant parameters for calculating method, and focused on the pharmacokinetics and population pharmacokinetics basic research methods, especially the nonlinear mixed effect method (NONMEM) which the most widely used method. This paper studies the core algorithm of NONMEM that based extended least squares. It points out the insufficiency of the several algorithms by comparing several different methods, and a new algorithm that based on improved nonlinear simplex method was proposed and was verified.
This paper carries on the following works:
(1) It shows the significance of the research of the population pharmacokinetics, shows the related concepts and knowledge in detail, and analyses the research and development status about population pharmacokinetics at home and abroad at present.
(2) Research-emphasis is the algorithm of NONMEM. The core fitting algorithm of NONMEM was studied and improved through the use of improved nonlinear simplex method, and reduces the amount of computation through conversion issues for the sake of the optimal solution.
(3) Improve the existing algorithms through add a new judgment direction, and improve the extension part of the nonlinear simplex method, and ensure that there is no degradation about the final simplex.
引文
[1]Niazi S.Textbook of Biopharmaceutics and Clinical Pharmacokinetics.New York:Division of Prentice Hall,Inc.,1979.141
[2]Sheiner LB,et al.Modeling of Pharmacoldnetics and pharmacodynamics:application to d-tubocurarine.Clin Pharmacol Ther,1979,25:358-371
[3]Center for Drug Evaluation Research.Guidance for industry:Population pharmacokinetics:DRAFT GUIDANCE,United States Department of Health and Human Services,Food and Drug Administration,1997
[4]Davidian M,et al.Some general estimation methods for nonlinear mixed effects models.Journal of Biopharmaceutical Statistics,1993,3:23-55
[5]芮建中.群体药动学-药效学原因及应用进展.国外医学药学分册,1995;22(5):227
[6]Sheiner LB,Grasela TH.An introduction to mixed effect modeling:concepts,definitions,and justification.J Pharmacokinet Biopharm,1991;19(3):11S-24S
[7]Davidian M,et al.Monographs on Statistics and Applied Probability(Volume 62)[M]:Nonlinear Models for Repeated Measurement Data.London:Chapman & Hall,1995.
[8]刘钦圣.最小二乘问题计算方法[M].北京:北京工业大学出版社,1989,72-153。
[9]胡敏,张静华,孙鹤,施孝金,钟明康.群体药动学原理及NONMEM法数据分析[A].药学服务与研究,2002,2(4):227-230。
[10]孔锐睿,仇汝臣,周田惠.非线性单纯形的修改算法[J].青岛大学学报,2002,15(3):41-44.
[11]M..吉伯尔迪等著,朱家壁译.药物动力学.第二版.北京:科学出版社,1987.164-305
[12]Sharhel L著,李安良译.应用生物药剂学与药物动力学.北京:中国医药出版社,1989.78
[13]Gibaldi M,Perrier D.Pharmacokinetics.New York:Marcel Dekker,1982,17
[14]周怀悟,薛祉绥,吴季俭.临床药学的数学原理和方法重庆:科学校术文献出版社重庆分社,1987.129
[15]Grasela TH,Antal EJ,Townsend RJ and Smith RB.An evaluation of population pharmacokinetics in therapeutic trials.Part I.Comparison of methodologies.Clin Pharmacol Ther,1986,39:605-612
[16]李元敏.群体药动学:理论与实践.国外医学药学分册,1992;19(5):288-290
[17]曾衍霖.临床药物动力学中群体及个体参数的估算.中国临床药理学志,1986;2(1):24-31
[18]李珍。群体药动学研究中非线性混合效应模型法的评价和应用.国外医学药学分册,1993;20(4):195-199
[19]程坤,朱家壁.群体药动学研究方法的比较和评价.中国药师,1999;2(1):45-48
[20]Rosenbanm S,Carter A and Dudlley M.Population pharmacokinetics:fundamentals,methods and applications.Drug Dev and Industrial Pharm 1995;21(9):1115-21
[21]Mallet A,et al.Nonparametric maximum-likelihood estimation for population pharmacokinetics with application to cyclospodne.J Pharmacokinet Biopharm 1988;16:311-327
[22]Mallet A.A maximum likelihood estimation method for random coefficient regression models.Biometrika 1986;73:645-656
[23]Schumitzky A.Nonparametric EM algorithms for estimating prior distributions.Applied Mathematics and Computation 1991;45:141-157
[24]Davidian M and Gallant AR.Smooth nonparametric maximum likelihood estimation for population pharmacokinetics,with application to quinidine.J Pharmacokinet Biopharm 1992;20:529-56
[25]Best N,Tan K,Gilks W,et al.Estimation of population pharmacokinetics using the Gibbs sampler.J Pharmacokinet Biopharm 1995;23(4):407-417
[26]Sheiner LB.Rosenberg R,Marathe VV.Estimation of population characteristics of pharmacokinetic parameters from routine clinical data.J Pharmacokinet Biopharm 1977;5:445-479
[27]Wade J,Beal S,Sambol N.Interaction between structural,statistical and covariate models in population pharmacokinetics analysis.J Pharmacokin Biopharm 1994;22(2):165-177
[28]Bruno R,Vivier N,Vergniol JC,Phillips SLD,Montay G,Sheiner LB.A population pharmacokinetic model for docetaxel(taxotere):Model building and validation.J Pharmacokin Biopharm 1996;24:153-172
[29]Karlsson MO,Sheiner LB.The importance of modeling intercession variability in population pharmacokinetic analyses.J Pharmacokin Biopharm 1993;21:735-750
[30]Roecker EB.Prediction error and its estimation for subset-selected models.Technometrics 1991;33:459-468
[31]Efron B.Estimating the error rate of a prediction rule:improvement on crossvalidation.J of the American Statistical Association 1983;78:316-331
[32]Ette EL.Population model stability and performance.J Clin Pharmacol 1997;37:486-495
[33]Vozeh S,Maitre PO,Stanski DR.Evaluation of population(NONMEM)pharmacokinetics parameters.J Pharmacokin Biopharm 1990;18:161-173
[34]Sheiner LB,Beal SL.Some suggestion for measuring predictive performance.J Pharmacokin Biopharm 1981;9:503-512
[35]Sheiner LB.Pharmacokinetic parameter estimates from several least squares procedures:Superiority of extend least squares.J Pharmacokinet Biopharm 1985;13(2):185-198
[36]袁亚湘.非线性规划数值方法[M].上海:上海科学技术出版社,1993,77-135.
[37]张可村,李换琴.工程优化方法及其应用[M].西安:西安交通大学出版社,2007,50-80.
[38]谢政,李建平,汤泽滢.非线性最优化[M].长沙:国防科技大学出版社,2003,209-237.
[39]Curry H B.The method of steepest descent for non linear minimization problems.Quart.Appl.Math.,2(1994),258-261.
[40]Spendley W,Hext G R,Himsworth F R.Sequential application of simplex designs in optimization and evolutionary operation.Technometrics,4(1962),441-461.
[41]俞文魮.单纯形调优法的收敛性质.中国科学,1979,数学专刊(I).
[42]杨高波,亓波.精通MATLAB7.0混合编程[M].北京:电子工业出版社,2006,108-122
[43]魏树理,张强.生物药剂学与药物动力学[M].北京:北京人学医学出版社,2004,238-271.
[2]Sheiner LB,et al.Modeling of Pharmacoldnetics and pharmacodynamics:application to d-tubocurarine.Clin Pharmacol Ther,1979,25:358-371
[3]Center for Drug Evaluation Research.Guidance for industry:Population pharmacokinetics:DRAFT GUIDANCE,United States Department of Health and Human Services,Food and Drug Administration,1997
[4]Davidian M,et al.Some general estimation methods for nonlinear mixed effects models.Journal of Biopharmaceutical Statistics,1993,3:23-55
[5]芮建中.群体药动学-药效学原因及应用进展.国外医学药学分册,1995;22(5):227
[6]Sheiner LB,Grasela TH.An introduction to mixed effect modeling:concepts,definitions,and justification.J Pharmacokinet Biopharm,1991;19(3):11S-24S
[7]Davidian M,et al.Monographs on Statistics and Applied Probability(Volume 62)[M]:Nonlinear Models for Repeated Measurement Data.London:Chapman & Hall,1995.
[8]刘钦圣.最小二乘问题计算方法[M].北京:北京工业大学出版社,1989,72-153。
[9]胡敏,张静华,孙鹤,施孝金,钟明康.群体药动学原理及NONMEM法数据分析[A].药学服务与研究,2002,2(4):227-230。
[10]孔锐睿,仇汝臣,周田惠.非线性单纯形的修改算法[J].青岛大学学报,2002,15(3):41-44.
[11]M..吉伯尔迪等著,朱家壁译.药物动力学.第二版.北京:科学出版社,1987.164-305
[12]Sharhel L著,李安良译.应用生物药剂学与药物动力学.北京:中国医药出版社,1989.78
[13]Gibaldi M,Perrier D.Pharmacokinetics.New York:Marcel Dekker,1982,17
[14]周怀悟,薛祉绥,吴季俭.临床药学的数学原理和方法重庆:科学校术文献出版社重庆分社,1987.129
[15]Grasela TH,Antal EJ,Townsend RJ and Smith RB.An evaluation of population pharmacokinetics in therapeutic trials.Part I.Comparison of methodologies.Clin Pharmacol Ther,1986,39:605-612
[16]李元敏.群体药动学:理论与实践.国外医学药学分册,1992;19(5):288-290
[17]曾衍霖.临床药物动力学中群体及个体参数的估算.中国临床药理学志,1986;2(1):24-31
[18]李珍。群体药动学研究中非线性混合效应模型法的评价和应用.国外医学药学分册,1993;20(4):195-199
[19]程坤,朱家壁.群体药动学研究方法的比较和评价.中国药师,1999;2(1):45-48
[20]Rosenbanm S,Carter A and Dudlley M.Population pharmacokinetics:fundamentals,methods and applications.Drug Dev and Industrial Pharm 1995;21(9):1115-21
[21]Mallet A,et al.Nonparametric maximum-likelihood estimation for population pharmacokinetics with application to cyclospodne.J Pharmacokinet Biopharm 1988;16:311-327
[22]Mallet A.A maximum likelihood estimation method for random coefficient regression models.Biometrika 1986;73:645-656
[23]Schumitzky A.Nonparametric EM algorithms for estimating prior distributions.Applied Mathematics and Computation 1991;45:141-157
[24]Davidian M and Gallant AR.Smooth nonparametric maximum likelihood estimation for population pharmacokinetics,with application to quinidine.J Pharmacokinet Biopharm 1992;20:529-56
[25]Best N,Tan K,Gilks W,et al.Estimation of population pharmacokinetics using the Gibbs sampler.J Pharmacokinet Biopharm 1995;23(4):407-417
[26]Sheiner LB.Rosenberg R,Marathe VV.Estimation of population characteristics of pharmacokinetic parameters from routine clinical data.J Pharmacokinet Biopharm 1977;5:445-479
[27]Wade J,Beal S,Sambol N.Interaction between structural,statistical and covariate models in population pharmacokinetics analysis.J Pharmacokin Biopharm 1994;22(2):165-177
[28]Bruno R,Vivier N,Vergniol JC,Phillips SLD,Montay G,Sheiner LB.A population pharmacokinetic model for docetaxel(taxotere):Model building and validation.J Pharmacokin Biopharm 1996;24:153-172
[29]Karlsson MO,Sheiner LB.The importance of modeling intercession variability in population pharmacokinetic analyses.J Pharmacokin Biopharm 1993;21:735-750
[30]Roecker EB.Prediction error and its estimation for subset-selected models.Technometrics 1991;33:459-468
[31]Efron B.Estimating the error rate of a prediction rule:improvement on crossvalidation.J of the American Statistical Association 1983;78:316-331
[32]Ette EL.Population model stability and performance.J Clin Pharmacol 1997;37:486-495
[33]Vozeh S,Maitre PO,Stanski DR.Evaluation of population(NONMEM)pharmacokinetics parameters.J Pharmacokin Biopharm 1990;18:161-173
[34]Sheiner LB,Beal SL.Some suggestion for measuring predictive performance.J Pharmacokin Biopharm 1981;9:503-512
[35]Sheiner LB.Pharmacokinetic parameter estimates from several least squares procedures:Superiority of extend least squares.J Pharmacokinet Biopharm 1985;13(2):185-198
[36]袁亚湘.非线性规划数值方法[M].上海:上海科学技术出版社,1993,77-135.
[37]张可村,李换琴.工程优化方法及其应用[M].西安:西安交通大学出版社,2007,50-80.
[38]谢政,李建平,汤泽滢.非线性最优化[M].长沙:国防科技大学出版社,2003,209-237.
[39]Curry H B.The method of steepest descent for non linear minimization problems.Quart.Appl.Math.,2(1994),258-261.
[40]Spendley W,Hext G R,Himsworth F R.Sequential application of simplex designs in optimization and evolutionary operation.Technometrics,4(1962),441-461.
[41]俞文魮.单纯形调优法的收敛性质.中国科学,1979,数学专刊(I).
[42]杨高波,亓波.精通MATLAB7.0混合编程[M].北京:电子工业出版社,2006,108-122
[43]魏树理,张强.生物药剂学与药物动力学[M].北京:北京人学医学出版社,2004,238-271.