药代动力学研究在新药研发中的应用

本文综述了药代动力学研究的内容、临床前药代动力学试验，组合给药的药代动力学研究，ADME过程的体外预测方法等方面的研究进展和应用实例，强调了药代动力学研究在新药研发中的意义和发展方向。     

群体药代动力学在临床药学中的应用

群体药代动力学(Population Pharmacoki-netics)较经典药代动力学(Classical Pharma-cokinetics)是一年轻的药学分支学科,它的发展仅有十几年的历史。Sheiner等将经典的药代动力学模型与群体统计学模型(Population Statis-tical Model)结合起来,提供了群体药代动力学理论,主要研究人体药代动力学参数的群体值,再结合病人的个体信息的反馈,得到病人的个体药代动力学参数,以优化给药方案,指导临床个体化用药。1 清除率概念在药代动力学中的应用 药物从人体内清除是多途径的。通常是以肾清除和肝清除为主。当一个药物经主要的代谢途径消除时,病人间消除的个体差异是普遍存在的。药物主要以肾排泄消除时,则肌酐清除     

药代动力学人体预测及其在新药研发中的应用

药物代谢和药代动力学(DMPK)通过揭示药物的体内代谢处置过程,理解药物药理效应和毒副反应的体内物质基础,是连接药物分子及其性质与生物学效应的桥梁。DMPK人体预测应用模型拟合技术,由人体外试验数据和动物体内外数据预测人体药代动力学性质,并与药效动力学和毒性评价相关联,可提高新药研发效率、降低临床失败率和节省资源。经典的异速放大法和体外-体内外推法主要用于预测人体清除率和稳态表观分布容积等重要的药代动力学参数。近10年来,基于生理的药代动力学模型(PBPK)的快速发展和应用实践,推动了DMPK人体预测在新药研发、药物监管、临床合理和个体化用药中的应用。PBPK模型不仅能预测消除和分布等参数,还能用于药物人体药代动力学行为的预测,包括血药浓度-时间曲线和药物-药物相互作用,以及不同人群体内药代动力学和药代-药效预测。作为新药研发的转化科学技术以及个体化用药的指导工具,DMPK人体预测将具有更为广泛的应用价值。     

群体药代动力学在临床药学中的应用

群体药代动力学(Population Pharmacokinetics)较经典药代动力学(Classical Pharmacokinetics)是一年轻的药学分支学科．它的发展仅有十几年的历史。Sheiner等将经典的药代动力学模型与群体统计学模型(Population Statistical Model)结合起来，提供了群体药代动力学理论，主要研究人体药代动力学参数的群体值，再结合病人的个体信息的反馈，得到病人的个体药代动力学参数，以优比给药方案，指导临床个体化用药。     

非线性混合效应模型法在群体药代动力学和群体药效学中的研究进展

群体药代动力学和群体药效学是近年来得到快速发展的药学领域，具有广阔的应用前景。本文对群体药代动力学和群体药效学重要估算方法非线性混合效应模型法进行综述，包括基本概念、常用模型、模型确定方法、数值计算和应用等方面。     

抗癫痫药的群体药代动力学与CYP450基因多态性的研究进展

抗癫痫药代谢的个体差异较大，需要个体化用药。群体药代动力学的研究是设计个体化治疗方案的有效方法。国内外对新老抗癫痫药的群体药代动力学进行了广泛研究，分析了一般生物学特征对药物代谢的影响。CYP450基因多态性是影响抗癫痫药物代谢的主要遗传因素，是个体差异的重要原因。目前，已有研究将CYP450基因多态性的因素引入群体药代动力学的模型，将其对抗癫痫药物代谢的影响进行了量化，并且，可以依据不同的基因型选择不同的初始剂量，促进个体化治疗，取得了新的进展。但是，有项研究提示基因多态性对群体药代动力学（PPK）参数的影响没有统计学意义。因此，目前的结论尚不完全一致，需要进一步研究。     

药代动力学建模的人工神经网络新方法

人工神经网络(ANN)在药代动力学领域主要用于血药浓度预测、药物结构和药代动力学定量关系、体内体外相关关系研究,群体药物动力学数据分析、药代动力学-药效动力学统一模型研究等。本文就ANN的基本理论及其在药代动力学研究的应用作简要综述。     

丙戊酸群体药代动力学研究进展

丙戊酸是广谱抗癫疒间药,临床应用广泛。该药体内代谢个体差异大,治疗窗窄,需要个体化治疗。丙戊酸体内代谢受多种因素影响,大量研究报道了丙戊酸群体药代动力学参数及其在个体化治疗中的应用。本文分别从人口学因素、遗传因素及合并用药等方面,对丙戊酸群体药代动力学研究及应用进行综述,为临床制定合理、安全的给药方案提供参考。     

抗癫痫新药托吡酯药代动力学研究现状

本综述了抗癫痫新药托吡酯近年来药代动力学的研究现状。从单剂量、多剂量以及与其它药物联合应用时药动学参数的确定，到各种因素如年龄、疾病等影响下药动学参数的改变，揭示出该药在正常人体及病态下体内代谢、排泄的规律，为我国癫痫病患临床合理用药提供参考资料。     

微透析在药代动力学研究中的应用

微透析是一较新的组织间隙液采样技术，近几年来在体微透析技术在药代动力学和药效学的研究中被广泛应用，本文描述了微透析采样的原理及其在药代动力学中的应用特点，并对其在人体药代动力学研究中的应用进行了介绍。     

药物动力学和药效动力学在抗菌药物新药开发和临床治疗上的应用

制定合理的给药方案是抗菌药物开发中临床试验成败的关键。近十年来群体药物动力学和药效动力学的发展和在抗菌药新药开发上的应用，对抗菌药物合理给药方案的制定有了突破性进展，已基本上形成了抗菌药物新药开发的一个模式。这一模式以药动药效学理论指导下的体外动力学模型、动物体内感染模型和Ⅰ期临床药动学试验为基础，以随机化统计模型和蒙地卡罗模拟为手段对Ⅲ期临床试验的给药方案进行统计比较以确定最佳的给药剂量和频率。本文系统性地描述如何从临床前和临床试验中获得准确可靠的数据进而建立药动药效学数学模型，着重于阐述抗菌药物药效学的基本概念、试验方法学的基本原理并简单介绍药动药效学的计算方法.     

Effect of cardiopulmonary bypass on cytochrome P450 enzyme activity: implications for pharmacotherapy

For patients undergoing cardiopulmonary bypass (CPB) during cardiac surgery, there are well-documented changes in the pharmacokinetics (PK) of commonly administered drugs. Although multiple factors potentially underpin these changes, there has been scant research attention on the impact of CPB to alter the activities of cytochrome P450 (CYP) isoenzymes. PK changes during cardiac surgery with CPB have the potential to adversely affect the safety and efficacy of pharmacotherapy and increase the risk of drug–drug interactions. Clinically significant changes in drug PK during CPB are likely to be prominent for drugs where CYP metabolism is a major clearance (CL) mechanism. However, clinical data from patients undergoing CPB surgery in support of this hypothesis are lacking, leaving a significant knowledge gap. In this review, we address the effects of CPB on the release of pro-inflammatory cytokines, in surgeries with and without CPB, both pre and post initiation of surgery. We reviewed literature to explore the relationship between the release of pro-inflammatory cytokines, and the expression and activities of CYP enzymes. Through this approach, we provide new insight on the effects of CPB on the PK of drugs administered to patients in the clinical setting. Future research to address this knowledge gap will have considerable impact to assist clinicians with optimizing pharmacotherapy in this patient population.     

A physiologically based pharmacokinetic (PBPK) approach to evaluate pharmacokinetics in patients with cancer

Potential differences in pharmacokinetics (PK) between healthy subjects and patients with cancer were investigated using a physiologically based pharmacokinetic approach integrating demographic and physiological data from patients with cancer. Demographic data such as age, sex and body weight, and clinical laboratory measurements such as albumin, alpha‐1 acid glycoprotein (AAG) and hematocrit were collected in ~2500 patients with cancer. A custom oncology population profile was built using the observed relationships among demographic variables and laboratory measurements in Simcyp® software, a population based ADME simulator. Patients with cancer were older compared with the age distribution in a built‐in healthy volunteer profile in Simcyp. Hematocrit and albumin levels were lower and AAG levels were higher in patients with cancer. The custom population profile was used to investigate the disease effect on the pharmacokinetics of two probe substrates, saquinavir and midazolam. Higher saquinavir exposure was predicted in patients relative to healthy subjects, which was explained by the altered drug binding due to elevated AAG levels in patients with cancer. Consistent with historical clinical data, similar midazolam exposure was predicted in patients and healthy subjects, supporting the hypothesis that the CYP3A activity is not altered in patients with cancer. These results suggest that the custom oncology population profile is a promising tool for the prediction of PK in patients with cancer. Further evaluation and extension of this population profile with more compounds and more data will be needed. Copyright © 2012 John Wiley & Sons, Ltd.     

用群体药代动力学模型实现抗生素个体化给药

目的:介绍群体药代动力学模型在抗生素调整剂量上的应用。方法:群体药代动力学模型以及药代动力学(PK)-药效动力学(PD)模型的基本概念、建立步骤、应用特点以及国内外发展现状。并通过两个举例说明剂量调试方法。结果与结论:群体药代动力学和TDM监测紧密联系用于临床抗感染治疗,PK-PD模型的应用有利于临床药学的剂量设计和剂量调整,为不同患者群体的抗感染治疗的最合理解释。     

Evaluation of Altered Drug Pharmacokinetics in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) is a life‐support modality used in patients with refractory cardiac and/or respiratory failure. A significant resurgence in the use ECMO has been seen in recent years as a result of substantial improvements in technology and survival benefit. With expanding ECMO use, a better understanding of how ECMO affects drug pharmacokinetics (PK) is necessary. The vast majority of PK studies in patients receiving ECMO have been conducted within neonatal or pediatric populations or within a controlled environment (e.g., in vitro or ex vivo). Because of significant differences in absorption, distribution, metabolism, and excretion, it may be inappropriate to extrapolate these PK data to adults. Thus, the aims of this review are to evaluate the changes in drug PK during ECMO and to summarize the available PK data for common drugs used in the adult critically ill patients during ECMO support. A search of the PubMed (1965–July 2016), EMBASE (1965–July 2016), and Cochrane Controlled Trial Register databases was performed. All relevant studies describing PK alterations during ECMO in ex vivo experiments and in adults were included. Evaluation of the data indicated that drug PK in adults receiving ECMO support may be significantly altered. Factors influencing these alterations are numerous and have intricate relationships with each other but can generally be classified as ECMO circuit factors, drug factors, and patient factors. Commonly used drugs in these patients include antimicrobials, sedatives, and analgesics. PK data for most of these drugs are generally lacking; however, recent research efforts in this patient population have provided some limited guidance in drug dosing. With an improved understanding of altered drug PK secondary to ECMO therapy, optimization of pharmacotherapy within this critically ill population continues to move forward.     

Successful Prediction of Human Pharmacokinetics by Improving Calculation Processes of Physiologically Based Pharmacokinetic Approach

The physiologically based pharmacokinetics (PBPK) model is a major mechanistic approach for predicting human pharmacokinetics (PK) using drug-specific and physiological parameters but has been difficult to use for human PK prediction with acceptable accuracy. Here, we report a newly developed PBPK approach that incorporates the mechanism of albumin-mediated membrane penetration in the liver and interspecies correlation for unbound tissue fractions. To verify the utility of our PBPK approach, we used 12 drugs that are mainly eliminated by hepatic metabolism to compare the prediction accuracy with a conventional PBPK approach and to observe human PK parameters. We found the predictive accuracy for total clearance (CL_tot), distribution volume at the steady state (V_ss), elimination half-life (t_1/2), and plasma concentration at the last measurable time point (C_last) of our PBPK approach to show better absolute average fold error and percentage within 2-fold error (1.6-1.8 and 67%-92%, respectively) compared with values obtained from the conventional PBPK approach (2.1-2.4 and 42%-67%, respectively). As our approach can use parameters obtained in early drug screening, it could help accelerate successful nomination of drug candidates by optimizing the pharmacokinetics of new chemical entities by directly using predicted human PK profiles.     

基于仿真的靶点介导药物处置模型简化分析（英文）

靶点介导的药物处置模型(Target-mediated drug disposition, TMDD)是研究单克隆抗体非线性PK的主要模型理论之一。然而全量TMDD模型参数较多,有限的临床数据并不能支持模型估算全部参数。因此,本研究旨在通过公式推导和模型仿真探讨TMDD模型的简化方法,提升TMDD模型在有限临床数据建模中的适用性。基于一项关于地诺单抗(denosumab)TMDD模型研究的结果及其模型参数,在群体水平上和个体水平上进行仿真分析。然后,利用准稳态近似模型,在模型拟合和参数估计的稳定性上,检验受体总浓度的两种假设的影响。结果表明,在治疗剂量下,总受体浓度对药物浓度变化的影响很小,而假设恒定总受体浓度的模型具有相同的预测能力。该简化方法可应用于单抗类药物研发中合理实验设计的制定和最优PK模型的选择。     

A pragmatic approach to the design of population pharmacokinetic studies

The publication of a seminal article on nonlinear mixed-effect modeling led to a revolution in pharmacokinetics (PKs) with the introduction of the population approach. Since then, interest in obtaining accurate and precise estimates of population PK parameters has led to work on population PK study design that extended previous work on optimal sampling designs for individual PK parameter estimation. The issues and developments in the design of population PK studies are reviewed as a prelude to investigating, via simulation, the performance of 2 approaches (population Fisher information matrix D-optimal design and informative block [profile] randomized [IBR] design) for designing population PK studies. The results of our simulation study indicate that the designs based on the 2 approaches yielded efficient parameter estimates. The designs based on the 2 approaches performed similarly, and in some cases designs based on the IBR approach were slightly better. The ease with which the IBR designs can be generated makes them preferable in drug development, where pragmatism and time are of great consideration. We, therefore, refer to the IBR designs as pragmatic designs. Pragmatic designs that achieve high efficiency in the estimation parameters should be used in the design of population PK studies, and simulation should be used to determine the efficiency of the designs.     

肾移植患者西罗莫司的群体药动学研究

目的:建立中国肾移植患者西罗莫司的群体药动学模型,为实施个体化用药提供理论支持。方法:选择47名肾移植术后采用西罗莫司+泼尼松+环孢素或他克莫司或霉酚酸酯(MMF)三联免疫抑制治疗的患者为研究对象,回顾性收集47名患者服药后的101个西罗莫司稳态血药浓度及相应的试验室检查数据,运用Winnonmix药动学软件,采用非线性混合效应模型(NONMEM)分析体重、年龄、性别、给药剂量、合并用药、肌酐清除率等对药动学参数的影响。最终模型的验证采用Jackknife法进行内部验证。结果:西罗莫司符合无滞后时间的一级消除动力学一室模型。固定效应结果量子,合用MMF和体重可影响药物清除率。最终模型公式为:CL/F(L·h-1)=11.01×0.14MMF+0.089×W。CL/F和Vd/F的群体典型值分别是11.01L·h-1和3616L,个体间变异分别为62.82%和85.07%。观测值和预测值间的残差(SD)和相关系数(r)分别是1.0ng·mL-1和0.94。结论:所建立的群体药动学模型能较好地估算服用西罗莫司的肾移植患者的个体及群体药动学参数,对指导临床个体化用药具有重要意义。