群体模型与个体化给药

1、群体药物动力学模型及其在儿童个体化用药中的应用李新刚北京天坛医院药学部2015.9.20目 录p群体药物动力学模型p基于模型的个体化用药模型是对于真实世界的一种抽象模拟。什么是模型？Science? Art?生活中模型无所不在：印象，经验，看法，成见，感悟节气，阴历，阳历文学艺术创作 什么是模型？All Models Are Wrongbut Some Are Useful实际观测值 = 模型预测值 + 实际观测值 = 模型预测值 (1 + )什么是模型？生活中的模型（预测，仿真）建议，预测，推测， 民谚农谣，一叶知秋，占扑，因为 ，所以 模型有什么用？预测，仿真 )Ypred -(Yobs

2、)Ypred -(Yobs Oii1TiiFV)()(1PpopPPpopPjTj贝易斯评估法 (Bayesian Estimation) 贝易斯定理根据某一事件以往发生的概率特征 (前置分布) 来预测其今后发生的可能性 (后发概率) /wiki/Thomas_BayesAdd Your Text定量药理学Pharmacometrics 定量药理学以数学和统计方法来描述、理解和预测药物的药物动力学和药效动力学行为，并对其中的信息的不确定性进行量化。 定量药理学使得新药研发和药物治疗中基于数据的决策更为合理。 应用领域： 临床药学 新药研发7Add Y

3、our Text定量药理学定量研究解析药理学现象的边缘交叉学科It is only when mathematics applied to it that a science is mature.一种科学只有在成功地运用数学时，才达到臻于成熟的地步。-拉法格:忆马克思8Add Your TextLewis SheinerMats KarlssonBill JuscoNick Holford定量药理学定量研究解析药理学现象的边缘交叉学科9Add Your Text定量药理学定量研究解析药理学现象的边缘交叉学科历史沿革 (国际)1970年代-Pharmacometrics1970年代-群体药物动力

4、学/NONMEM1970/80年代-药物动力学/药效动力学(PKPD) 美国的FDA/CDER 1987-生物药剂学部门（Division of Biopharmaceutics） 2009-定量药理学部门（Division of Pharmacometrics）10定量药理学定量研究解析药理学现象的边缘交叉学科 生物药剂学 药物动力学 群体药物动力学 药动学/药效学 模型化/仿真定量药理学核心学科11药物动力学Pharmacokinetics，PK 应用动力学原理阐明药物的体内过程，定量研究药物在生物体内吸收、分布、代谢和排泄（ADME）诸过程随时间变化的规律，并以数学模型进行表述。12药物

5、动力学研究中的静注一室模型 (Bolus)KX, - dtdXXoX)0( ，tXXodtKXdX0tK-0LnXoLnX-KteXoXKt-Kt-eCoeVXoC13药物动力学中的各种房室模型， 14药物动力学中的各种房室模型Dose (LPV)CLPV, VLPV/FDose(RTV)CentralCRTV, VC,RTV/FA1AnAbsorptionPeripheralCP,RTV, VP,RTV/FCLLPV/FkaLPVkaRTVCLRTV/FQ/FRifampicinhillRTVhillhillRTVMAXLPVCECCECLCL5001bioavailabilitybioav

6、ailability clearance clearance bioavailabilityktrktrktrInhibition bioavailability Only for Children15Pharmacometrics 生物药剂学 药物动力学 群体药物动力学 药动学/药效学 模型化/仿真定量药理学核心学科16经典药物动力学 - 群体药物动力学iktKiExpViXoiCikijkijkijKijViBWijtExpKpopExpExpBWVpopXoCijk)()()70(1 17群体药物动力学的研究目的更加深入完整地理解药物的体内过程1观测病人群体的药物动力学和药效动力学的整体

7、特征 3分别评估个体间、个体内随机变异性的影响2观察相关因素(固定效应)对於群体药物动力学和药效动力学的影响18药物动力学中群体、亚群体与个体的关系)()70(1 ijViBWijExpBWVpopV群体群体亚群体亚群体i个体个体j19PopPK研究方法、对象对药物体内过程可能产生影响的因素群体药物动力学群体药物动力学研究对象研究对象Add Your Text固定效应因素 个体间变异 随机效应因素 个体间变异 个体内/试验间变异血药浓度-时间Non-linear Mixed Effect Modeling (NONMEM)非线性混合效应模型法20固定效应因素-易测量，相对稳定生理学因素病理学因

8、素环境因素年龄、性别、体重、种族、肝肾功能、习惯嗜好(烟、酒、茶、橙汁饮料)等疾病种类、程度、并发症、合并用药等实验人员、场所、时间、药品批次、来源等21固定效应因素对药物体内过程的影响方式 连续性变化因素-年龄、体重、肝肾功能等非连续性变化因素-种族、嗜好、性别等固定效应) 8 .20BMI( )8 .20(1 (BMIiCLpopCLpopiBMI8 .20/iBMIBMICLpopCLi）（8 .20MIeiBBMICLpopCLi22固定效应因素对药物体内过程的影响方式 连续性变化因素-年龄、体重、肝肾功能等非连续性变化因素-种族、嗜好、性别等固定效应GNDRiGNDRFCLCLima

9、le if 1or female if 0GNDR，23PopPK研究方法、对象对药物体内过程可能产生影响的因素群体药物动力学群体药物动力学研究对象研究对象Add Your Text固定效应因素 个体间变异 随机效应因素 个体间变异 个体内/试验间变异血药浓度-时间Non-linear Mixed Effect Modeling (NONMEM)非线性混合效应模型法24随机效应因素相对难以预知，但符合某种分布特征个体间随机变异 : N(0,2)个体内/实验间随机变异 : N(0,2)目前尚且未知的生理病理状态、无法测定的病理或遗传学差异、不易察觉的环境变化，及无法避免的测量误差以及模型偏差随机

10、效应25药物动力学中的常用算法最小二乘法 (OLS)2)(iiiOLSYpredYobsOFV)(/)(2iiiiiELSVarLnVarYpredYobsOFV扩展最小二乘法 (ELS)26药物动力学中的常用算法 )Ypred -(Yobs )Ypred -(Yobs Oii1TiiFV)()(1PpopPPpopPjTj贝易斯评估法 (Bayesian Estimation) 贝易斯定理根据某一事件以往发生的概率特征 (前置分布) 来预测其今后发生的可能性 (后发概率) Thomas Bayes was the son of London Presbyterian minister Jos

11、hua Bayes2 and perhaps born in Hertfordshire.3 In 1719 he enrolled at theUniversity of Edinburgh to study logic and theology. On his return around 1722 he assisted his father at the latters non-conformist chapel in London before moving to Tunbridge Wells, Kent around 1734. There he became minister o

12、f the Mount Sion chapel until 1752.4He is known to have published two works in his lifetime, one theological and one mathematical:Divine Benevolence, or an Attempt to Prove That the Principal End of the Divine Providence and Government is the Happiness of His Creatures (1731)An Introduction to the D

13、octrine of Fluxions, and a Defence of the Mathematicians Against the Objections of the Author of the Analyst (published anonymously in 1736), in which he defended the logical foundation of Isaac Newtons calculus (fluxions) against the criticism ofGeorge Berkeley, author of The AnalystIt is speculate

14、d that Bayes was elected as a Fellow of the Royal Society in 1742 5 on the strength of theIntroduction to the Doctrine of Fluxions, as he is not known to have published any other mathematical works during his lifetime.In his later years he took a deep interest in probability. Stephen Stigler feels t

15、hat he became interested in the subject while reviewing a work written in 1755 by Thomas Simpson,6 but George Alfred Barnard thinks he learned mathematics and probability from a book by de Moivre.7 His work and findings on probability theory were passed in manuscript form to his friend Richard Price

16、 after his death.By 1755 he was ill and in 1761 had died in Tunbridge. He was buried in Bunhill Fields Cemetery in Moorgate, London where many Nonconformists lie./wiki/Thomas_Bayes27群体药物动力学（NONMEM法）特点小结对 于 富 集或 稀 疏 数据组(rich or sparse data set)均可分析可 对 各 固定 效 应 影响 进 行 统计学评价可分别进行个

17、 体 间 / 个体内随机变异水平的定量评估应用领域：1.新药评价2. 临床合理化用药28最终模型)()128(1 (1111/1/CLCLGNDRCLSCRExpGENDERfSCRifpopCLiCL)(222CLExppopCLiCL)(333CLExppopCLiCL)()41() 3 .71(1 (1111V/1V/VASTBWExpASTfBWifpopViV)(222VExppopViV)(333VExppopViV)(KaExpKapopKai)(FExpFpopFi29最终模型的图形评价30最终模型的验证内部验证外部验证：外部数据对模型进行验证杰克小刀BootstrapVPCN

18、PDE31目 录p群体药物动力学模型p基于模型的个体化用药癫痫是慢性反复发作性短暂脑功能失调综合征，丙戊酸是一线抗癫痫药物基于丙戊酸群体模型的个体化给药33 )Ypred -(Yobs )Ypred -(Yobs Oii1TiiFV)()(1PpopPPpopPjTj贝易斯评估法 (Bayesian Estimation) 根据某一事件以往发生的概率特征 (前置分布) 预测其今后发生的可能性 (后发概率) Thomas Bayes was the son of London Presbyterian minister Joshua Bayes2 and perhaps born in Hert

19、fordshire.3 In 1719 he enrolled at theUniversity of Edinburgh to study logic and theology. On his return around 1722 he assisted his father at the latters non-conformist chapel in London before moving to Tunbridge Wells, Kent around 1734. There he became minister of the Mount Sion chapel until 1752.

20、4He is known to have published two works in his lifetime, one theological and one mathematical:Divine Benevolence, or an Attempt to Prove That the Principal End of the Divine Providence and Government is the Happiness of His Creatures (1731)An Introduction to the Doctrine of Fluxions, and a Defence

21、of the Mathematicians Against the Objections of the Author of the Analyst (published anonymously in 1736), in which he defended the logical foundation of Isaac Newtons calculus (fluxions) against the criticism ofGeorge Berkeley, author of The AnalystIt is speculated that Bayes was elected as a Fello

22、w of the Royal Society in 1742 5 on the strength of theIntroduction to the Doctrine of Fluxions, as he is not known to have published any other mathematical works during his lifetime.In his later years he took a deep interest in probability. Stephen Stigler feels that he became interested in the sub

23、ject while reviewing a work written in 1755 by Thomas Simpson,6 but George Alfred Barnard thinks he learned mathematics and probability from a book by de Moivre.7 His work and findings on probability theory were passed in manuscript form to his friend Richard Price after his death.By 1755 he was ill and in 1761 had died in Tunbridge. He was buried in Bunhill Fields Cemetery in Moorgate, London where many Nonconformists lie./wiki/Thomas_Bayes34研究方法p患者筛选（北京天坛医院的住院癫痫患儿）p临床信息采集p药物浓度的测定（TDx）p软件（NONMEM、PsN、Excel、JPKD）p群体模型的建立（基础模型全量模型最终模型）p模型验证（Bootst