五种群体药动学分析工具计算结果的比较

目的：比较群体药动学分析工具Phoenix NLME、Monolix、R语言nlmixr包和CPhaMAS云平台所计算的结果与金标准NONMEM的符合程度。方法：基于一房室模型模拟50个稀疏采样数据集和二房室模型模拟50个密集采样数据集,分别使用上述五种分析工具计算,比较群体典型值、个体变异和个体药动学参数。结果：CPhaMAS和Phoenix NLME计算的群体典型值、个体变异与NONMEM的匹配程度最高,其次为nlmixr,Monolix最低,但Monolix和nlmixr的算法可能更稳健。清除率和分布容积的对应性优于吸收速率常数。除了Monolix计算的吸收速率常数和nlmixr计算的房室间清除率,所有分析工具计算的个体药动学参数相关系数均大于0.99。结论:上述四种群体药动学分析工具计算结果与NONMEM的结果高度相关。     

生理药动学模型预测阿戈美拉汀口服给药的体内药动学过程

目的:建立阿戈美拉汀在人体内的生理药动学(PBPK)模型,预测其口服给药后的体内药动学过程。方法:测定不同基因型群体的健康男性空腹口服阿戈美拉汀后的血药浓度,采用Gastro PlusTM软件建立阿戈美拉汀口服给药的PBPK模型,并进行模型的优化和验证。结果:模型拟合阿戈美拉汀的药-时曲线与实测值比较R2均>0.95。预测阿戈美拉汀口服给药后绝对生物利用度为1%~7%;给药后其在人体内广泛分布,各组织/器官的暴露量以肝、脑和红骨髓中为最高,约为血中药物暴露量的2~4倍;食物、年龄、性别均可对阿戈美拉汀口服给药后的药动学过程产生一定的影响。结论:该试验所建立的PBPK模型可较好模拟阿戈美拉汀的体内药动学过程。     

采用生理药动学模型预测新型泛磷酸二酯酶抑制剂ZSP1601在人体中的药动学

ZSP1601是一种新的泛磷酸二酯酶抑制剂,临床拟用于非酒精性脂肪肝炎的治疗,目前处于早期临床研究阶段.本文拟建立ZSP1601的人体生理药动学(PBPK)模型,用于预测药物在人体的药动学行为.首先根据非临床体外和体内实验结果建立大鼠和犬静脉及口服给药的PBPK模型.在此基础上构建人体PBPK模型,分别比较了体外体内外...     

生理药动学模型概况及应用

概括生理药动学模型在药毒物方面应用的现状,探讨推动药动学发展的途径与方向.在概述生理模型产生的背景、发展历史、基本特点及模型建立的基础上,评述生理模型近十年来在药毒物代谢与危险性评估方面的应用.     

妊娠期药动学变化与生理药动学模型在妊娠期药动学研究中的应用

妊娠妇女合理用药是医生和药师必须认真对待的临床问题。妊娠期间体内大多数组织器官都会发生解剖和生理学的改变,从而影响药物的吸收、分布、代谢和排泄等体内过程,最终导致生物利用度的变化。因此为达到有效治疗浓度,孕期可能需要剂量调整。过去的十几年中建模与仿真技术在新药研发和临床治疗领域的应用不断扩展,例如用群体药动学(population pharmacokinetics, PPK)和生理药动学(physiologically based pharmacokinetics,PBPK)建模方法来设计特殊人群的给药方案。严谨设计和验证的模型能有效弥补临床试验的不足,为临床研究方案设计提供极有价值的参考,甚至替代部分临床试验。本文将介绍妊娠期影响药物药动学性质的生理学变化,并综述PBPK模型在妊娠期药动学研究中的应用进展。     

药动学模型的辨识问题研究

目的:研究药动学房室模型的辨识问题。方法:采用Laplace变换方法对一次性给药的经典房室模型的辨识问题进行系统讨论。结果:一次性给药的经典房室模型一般不具有唯一性,存在房室模型的辨识问题。结论:在两种经典房室模型不可辨识的情况下,血药浓度与分布器官中药物浓度成正比,此时通过测定血药浓度来预测分布器官或靶器官中药物浓度是有理论根据和有意义的;反之,在两种经典房室模型可辨识的情况下,血药浓度与分布器官或靶器官中药物浓度不成比例关系,此时欲通过血药浓度监测来预测分布器官或靶器官中药物浓度,就需首先确定血药浓度与分布器官或靶器官中药物浓度之间的关系,否则是没有理论根据和无意义的。     

成人万古霉素群体药动学的研究进展

目的:为临床合理应用万古霉素提供参考。方法:以"成人""万古霉素""群体药动学""群体药动学模型""Adults""Vancomycin""Population pharmacokinetic""PPK model"等为中英文关键词,在PubMed、中国知网、万方等数据库中组合检索自建库起至2019年10月31日发表的相关文献,对成人万古霉素群体药动学(PPK)的研究进展进行综述。结果与结论:共检索到相关文献166篇,其中有效文献25篇。目前已有研究在成年感染患者、危重症患者、接受肾脏替代治疗及血液滤过治疗的患者、神经外科患者、接受体外膜氧合治疗的患者、重症脓毒血症患者、血液肿瘤患者以及下呼吸道感染重症患者等群体中建立了万古霉素PPK模型。成人患者中,肌酐清除率与体质量是影响万古霉素药动学参数的主要因素,提示临床用药时应当关注患者肾功能与体质量;另外,是否感染及感染类型也对万古霉素的药动学参数有不同程度的影响。对于接受肾脏替代治疗及血液滤过治疗的患者,万古霉素的清除主要与其疗法的滤过率相关,提示临床应当根据所接受疗法的滤过率调整剂量;对于神经外科患者,脑脊液白蛋白与脑脊液引流量则是万古...     

儿童生理药动学模型及其在儿科用药研究中的应用进展

在儿科用药研究中,儿童生理药动学(PBPK)模型已成为确定首次儿童用药剂量和指导儿童临床试验设计的一个重要方法。本文通过比较PBPK模型和房室模型,并结合既往的经验,重点从发育生理学和细胞色素P450酶的个体发生学等方面阐述儿童PBPK模型的特点,介绍儿童PBPK模型的建模策略、误区及注意事项,同时结合最新的文献实例和FDA审评观点,对其在儿科用药研究方面的前景进行了分析和探讨。     

群体药动学参数的估算与应用

群体药动学参数在给药个体化中,有着极其重要的地位.当病人明确诊断,选定药物后,首先根据群体药动学参数设计给药方案,如果群体代表性强,预报的血药浓度将接近期望值,不然会造成较大的误差。     

银屑病患者甲氨蝶呤的群体药动学研究

目的:研究银屑病患者甲氨蝶呤(MTX)的群体药动学特征,为临床调整个体化用药提供新途径。方法:收集皮肤科50例银屑病患者单剂量静脉滴注MTX后稀疏血药浓度数据137个,采用荧光偏振免疫法(FPIA)测定,应用非线性混合效应模型(NONMEM)程序一步法估算MTX的群体药动学参数,并定量分析患者年龄、性别、体质量、肌酐清除率、尿素氮等因素对MTX药动学参数的影响。结果:按静脉滴注二房室线性开放模型估算的群体药动学参数中央室清除率(CL)、中央室表观分布容积(Vc)、外周室表观分布容积(Vp)及外周室清除率(Q)分别为10.4L·h-1、11.7L、6.61L及2.8L·h-1,其个体间变异ωCL、ωVc、ωVp、ωQ分别为16.8%、2.8%、11.7%及287.9%。且最终回归模型的MTX浓度估算值与实测值具有一致性。效应中尿素氮对Vp的影响具有显著意义(P>0.05),其协变量参数为(尿素氮/4)-0.845。结论:NONMEM法以二室模型群体参数估算的血药浓度值与实测值有良好相关性,此研究结果有助于MTX的临床合理应用。     

Physiologically based pharmacokinetic modeling of cyclotrimethylenetrinitramine in male rats

A physiologically based pharmacokinetic (PBPK) model for simulating the kinetics of cyclotrimethylene trinitramine (RDX) in male rats was developed. The model consisted of five compartments interconnected by systemic circulation. The tissue uptake of RDX was described as a perfusion‐limited process whereas hepatic clearance and gastrointestinal absorption were described as first‐order processes. The physiological parameters for the rat were obtained from the literature whereas the tissue : blood partition coefficients were estimated on the basis of the tissue and blood composition as well as the lipophilicity characteristics of RDX (logP = 0.87). The tissue : blood partition coefficients (brain, 1.4; muscle, 1; fat, 7.55; liver, 1.2) obtained with this algorithmic approach were used without any adjustment, since a focused in vitro study indicated that the relative concentration of RDX in whole blood and plasma is about 1 : 1. An initial estimate of metabolic clearance of RDX (2.2 h^?1 kg^?1) was obtained by fitting PBPK model simulations to the data on plasma kinetics in rats administered 5.5 mg kg^?1 i.v. The rat PBPK model without any further change in parameter values adequately simulated the blood kinetic data for RDX at much lower doses (0.77 and 1.04 mg ^?1 i.v.), collected in this study. The same model, with the incorporation of a first order oral absorption rate constant (K_a 0.75 h^?1), reproduced the blood kinetics of RDX in rats receiving a single gavage dose of 1.53 or 2.02 mg kg^?1. Additionally, the model simulated the plasma and blood kinetics of orally administered RDX at a higher dose (100 mg kg^?1) or lower doses (0.2 or 1.24 mg kg^?1) in male rats. Overall, the rat PBPK model for RDX with its parameters adequately simulates the blood and plasma kinetic data, obtained following i.v. doses ranging from 0.77 to 5.5 mg kg^?1 as well as oral doses ranging from 0.2 to 100 mg kg^?1. Published in 2009 by John Wiley & Sons, Ltd.     

家兔体内呋喃苯胺酸的药动学和药效学结合模型

用药动学-药效学结合模型对呋喃苯胺酸在家兔体内的处置和效应动力学作定量分析。呋喃苯胺酸的k_(eo),S,E_(max),EC_(50)分别为0.131±0.029min~(-1),2.21±0.61,6.5±0.6ml/min,3.49±0.77μg/ml。结果表明血浆与作用部位属于不同的房室,两者之间存在着一个平衡过程。     

VolSurf软件及其在药物代谢性质虚拟高通量筛选中的应用

当前新药的研发模式发生了改变,需要药代动力学早期参与以减少损失。本文介绍了目前国外正在研究开发与应用的用于新药早期药代动力学虚拟高通量筛选的软件之一VolSurf的特点及其应用     

国内常用合理用药软件的综合评价

目的：介绍、评价国内应用较多的七款合理用药软件,为医疗机构选择合理用药软件提供参考。方法：通过文献检索和用户使用调查,从合理用药软件的数据库来源、功能模块、优势特点、版本更新和用户数量及使用体验等几个方面进行综合评价。结果：美德医系统较为先进,兼具专业性和灵活性的特点;美康、大通和逸曜国内用户最多;美康数据库信息全面并提供详细的更新说明;大通拥有庞大的循证医学信息资源,数据更新快,但售后服务不及时;逸曜由药师自主编程,采用智能推理技术,操作简单,售后服务及时;普华和诚、天际健康、慧药通在处方审核模块各有特色。结论：国内的合理用药软件具有相似的基本功能,并日趋完善,同时又有各自的特点和优势,提供了较为完备的市场选择。美康数据库完善,价格适中,适合大部分医院;天际健康能够提供个性化定制服务,逸曜能够实现药师自主编程,操作简单,这两款适合想建立自己特色数据库的医院。普华和诚运行速度块,能够实现专科化和中成药的审核,适合专科化审核要求高的医院;美德医具有针对医保和商保的智能审核系统,适合医院医保用来控费。     

Physiological modeling reveals novel pharmacokinetic behavior for inhaled octamethylcyclotetrasiloxane in rats.

Octamethylcyclotetrasiloxane (D4) is an ingredient in selected consumer and precision cleaning products. Workplace inhalation exposures may occur in some D4 production operations. In this study, we analyzed tissue, plasma, and excreta time-course data following D4 inhalation in Fischer 344 rats (K. Plotzke et al., 2000, Drug Metab. Dispos. 28, 192-204) to assess the degree to which the disposition of D4 is similar to or different from that of volatile hydrocarbons that lack silicone substitution. We first applied a basic physiologically based pharmacokinetic (PBPK) model (J. C. Ramsey and M. E. Andersen, 1984, Toxicol. Appl. Pharmacol. 73, 159-175) to characterize the biological determinants of D4 kinetics. Parameter estimation techniques indicated an unusual set of characteristics, i.e., a low blood:air (P(b:a) congruent with 0.9) and a high fat:blood partition coefficient (P(f:b) congruent with 550). These parameters were then determined experimentally by equilibrating tissue or liquid samples with saturated atmospheres of D4. Consistent with the estimates from the time-course data, blood:air partition coefficients were small, ranging from 1.9 to 6.9 in six samples. Perirenal fat:air partition coefficients were large, from 1400 to 2500. The average P(f:b) was determined to be 485. This combination of partitioning characteristics leads to rapid exhalation of free D4 at the cessation of the inhalation exposure followed by a much slower redistribution of D4 from fat and tissue storage compartments. The basic PK model failed to describe D4 tissue kinetics in the postexposure period and had to be expanded by adding deep-tissue compartments in liver and lung, a mobile chylomicron-like lipid transport pool in blood, and a second fat compartment. Model parameters for the refined model were optimized using single-exposure data in male and female rats exposed at three concentrations: 7, 70, and 700 ppm. With inclusion of induction of D4 metabolism at 700 ppm (3-fold in males, 1-fold in females), the parameter set from the single exposures successfully predicted PK results from 14-day multiple exposures at 7 and 700 ppm. A common parameter set worked for both genders. Despite its very high lipophilicity, D4 does not show prolonged retention because of high hepatic and exhalation clearance. The high lipid solubility, low blood:air partition coefficient, and plasma lipid storage with D4 led to novel distributional characteristics not previously noted for inhaled organic hydrocarbons. These novel characteristics were only made apparent by analysis of the time-course data with PBPK modeling techniques.     

A survey of population analysis methods and software for complex pharmacokinetic and pharmacodynamic models with examples

An overview is provided of the present population analysis methods and an assessment of which software packages are most appropriate for various PK/PD modeling problems. Four PK/PD example problems were solved using the programs NONMEM VI beta version, PDx-MCPEM, S-ADAPT, MONOLIX, and WinBUGS, informally assessed for reasonable accuracy and stability in analyzing these problems. Also, for each program we describe their general interface, ease of use, and abilities. We conclude with discussing which algorithms and software are most suitable for which types of PK/PD problems. NONMEM FO method is accurate and fast with 2-compartment models, if intra-individual and interindividual variances are small. The NONMEM FOCE method is slower than FO, but gives accurate population values regardless of size of intra- and interindividual errors. However, if data are very sparse, the NONMEM FOCE method can lead to inaccurate values, while the Laplace method can provide more accurate results. The exact EM methods (performed using S-ADAPT, PDx-MCPEM, and MONOLIX) have greater stability in analyzing complex PK/PD models, and can provide accurate results with sparse or rich data. MCPEM methods perform more slowly than NONMEM FOCE for simple models, but perform more quickly and stably than NONMEM FOCE for complex models. WinBUGS provides accurate assessments of the population parameters, standard errors and 95% confidence intervals for all examples. Like the MCPEM methods, WinBUGS's efficiency increases relative to NONMEM when solving the complex PK/PD models.     

常用他汀类药物的比较研究

他汀类药物是治疗高胆固醇血症的一线药物,也是心脑血管病一级和二级预防的最重要药物之一。不同他汀类药物在药动学、药效学方面存在差异,其不良反应对患者的健康也会产生一定的影响。本文总结了国内常用7种他汀类药物在药动学、临床应用、安全性方面的异同,以期为临床医师选择合适的降脂措施,降低不良反应发生率,提供参考。     

健康志愿者二甲双胍缓释片群体药动学模型的初步研究

目的 建立中国健康志愿者服用二甲双胍缓释片的群体药动学(PPK)模型,并研究不同生理因素对二甲双胍药动学参数的影响。方法 20名中国健康受试者(男性11名、女性9名),单剂量给予二甲双胍缓释片 1 000 mg,收集受试者服药后0~24 h血样标本,建立液相色谱-质谱/质谱(LC-MS/MS)方法测定人血浆二甲双胍浓度,采用非线性混合效应模型(NONMEM)建立二甲双胍的群体药动学(PPK)模型,并探讨生理因素对二甲双胍药动学的影响。结果 二甲双胍药动学符合一房室模型,清除率(CL/F)、分布容积(Vd/F)和吸收速率常数K_a分别为(95.8±7.46) L/h、(553±45.9) L及(0.596±0.070)/h。引入体重作为CL/F及Vd/F的协变量,使模型显著改善(P<0.05)。结论 NONMEM法可以用于二甲双胍药动学研究,且体重对二甲双胍清除率存在显著影响。     

A physiologically based pharmacokinetic model for polyethylene glycol-coated gold nanoparticles of different sizes in adult mice

Nanoparticles (NPs) are widely used in various fields of nanomedicine. A systematic understanding of NP pharmacokinetics is crucial in their design, applications, and risk assessment. In order to integrate available experimental information and to gain insights into NP pharmacokinetics, a membrane-limited physiologically based pharmacokinetic (PBPK) model for polyethylene glycol-coated gold (Au) NPs (PEG-coated AuNPs) was developed in mice. The model described endocytosis of the NPs in the liver, spleen, kidneys, and lungs and was calibrated using data from mice that were intravenously injected with 0.85?mg/kg 13?nm and 100?nm PEG-coated AuNPs. The model adequately predicted multiple external datasets for PEG-coated AuNPs of similar sizes (13–20?nm; 80–100?nm), indicating reliable predictive capability in suitable size ranges. Simulation results suggest that endocytosis of NPs is time and size dependent, i.e. endocytosis of larger NPs occurs immediately and predominately from the blood, whereas smaller NPs can diffuse through the capillary wall and their endocytosis appears mainly from the tissue with a 10-h delay, which may be the primary mechanism responsible for the reported size-dependent pharmacokinetics of NPs. Several physiological parameters (e.g. liver weight fraction of body weight) were identified to have a high influence on selected key dose metrics, indicating the need for additional interspecies comparison and scaling studies and to conduct pharmacokinetic studies of NPs in species that are more closely related to humans in these parameters. This PBPK model provides useful insights into the size, time, and species dependence of NP pharmacokinetics.