药动学-药效学结合模型的研究进展及应用

目的 综述药动学-药效学(PK-PD)结合模型的研究进展。方法 对近十年来国内外发表的具有代表性的相关文章进行分析、整理和归纳,总结PK-PD结合模型的类型、程序及应用。结果 PK-PD结合模型有4种类型,其在新药研发,个体化给药和临床检测等方面都有广泛的应用,为临床用药提供了有力的指导。结论 PK-PD模型随着研究的深入不断完善,在药物开发和研究中发挥了重要的作用。     

合理应用抗菌药物要点分析

目的 探讨合理应用抗菌药物须把握的要点.方法 通过临床实例对抗菌药物不合理用药情况进行分析并提出合理的建议.结果 某院在抗菌药物应用指征、药物选择、给药方案、联合用药及与其他药物相互作用等方面均存在不合理用药情况.结论 临床药师应熟练应用抗菌药物药效学及药动学知识,积极参与制定治疗方案,以促进抗菌药物的合理使用.     

整合动态PK-PD相关性分析在中药药效物质基础发现中的研究策略

中药药效物质基础研究是解释中医药作用机制的基石,然而中药复方作为一个复杂体系,作用机制与体内效应过程不明确等问题长期桎梏中医药事业的发展。药动学-药效学（PK-PD）相关性研究是动态表征和定量描述活性成分与药理作用之间相关性的有效方法,将时间、浓度和效应结合起来,已经成为阐明中药药效物质基础的技术策略,但是目前研究大都集中在结构明确的化学药物,缺乏符合中医药发展模式的相关策略。因此,非常有必要深入挖掘新的研究策略,建立符合中医药特色的PK-PD模型,通过进行方法开发与技术重组,利用从化学物质基础、关键成分的筛选、整合PK-PD相关性的多维整合的研究思路,引入代谢组学等现代技术手段,全方位、及时灵敏地表征药效特点,评价药动学考察药物机制研究,旨在构建更易于发现药效物质的技术体系,为阐明中药复方的药效物质基础提供参考。     

心血管系统药物的PK-PD模型研究进展

目的对心血管系统药物的药动学-药效学(PK-PD)模型研究进行回顾和展望。方法查阅文献资料,对相关内容进行总结。结果所得PK-PD模型以S-Emax模型居多。心血管系统药物的PK-PD模型日益呈现出精细化和复杂化的趋势。结论应用PK-PD模型对心血管系统药物的研究前景广阔,值得进一步推广。     

抗菌药物的药动学和药效学参数对临床用药的指导作用

目的 探讨抗菌药物的药动学/药效学(PK/PD)参数与临床用药方案的关系.方法 参阅相关文献,依据药效学和药动学理论,结合临床用药实际,确定抗茵药物的用药方案.结果 抗菌药物可分为浓度依赖性抗菌药物和时间依赖性抗菌药物.结论 依据PK/PD综合参数对制定合理给药方案、提高临床疗效有重要意义.     

抗菌药物的药动学及药效学相关研究的临床意义

通过对抗菌药物的药动学(PK)、药效学(PD)的相关研究，发现了抗菌药物不同的PK/PD特性；提出了预测抗菌药物疗效的重要PD参数为AUC0-24/MIC，Cmax/MIC，t＞MIC和抗生素后效应(PAE)等；而且对评价药物有效性。指导合理用药，提高药物疗效，避免产生耐药性都有指导性的作用。因此，PK/PD研究是抗菌药合理应用的基础，在研究、设计和制定抗菌药物治疗方案、制定敏感性临界值以及推荐用药指南等方面都具有重要价值。     

基于异植瘤小鼠的抗肿瘤药PK/PD模型:历史回顾、研究进展与应用实践

异植瘤小鼠是广泛应用于抗肿瘤研究的临床前疾病动物模型。基于异植瘤小鼠的抗肿瘤药PK/PD建模是一种利用异植瘤小鼠实验数据与非线性混合效应模型法描述给药后"剂量-血药浓度-生物标志物水平-肿瘤体积"经时过程的方法。可基于模拟优化剂量与给药方案,评价抗肿瘤治疗联合用药方案协同效能,搜寻优效联用剂量组合,初步预测药物在人体的有效剂量与抗肿瘤效能,定量地阐释药物作用于靶点后生物标志物浓度变化所驱动的肿瘤增长抑制机制。本文系统地回顾了主流抗肿瘤药PK/PD模型的诞生背景、适用范围与应用局限,详细综述了创新抗肿瘤药PK/PD模型研究进展,并从作用机制探索、联合用药优化以及临床转化预测方面列举了PK/PD模型在抗肿瘤药物研究中的应用实践。     

药代动力学和药效学结合模型的研究进展

药代动力学-药效学结合模型是将药代动力学和药效学结合起来研究的模型，能描述和预测一定剂量方案下药物的效应-时间过程，还能解释造成这种效应一时间过程的原因。这种结合模型可应用于药物开发的临床前和临床试验的各个阶段。在临床前试验阶段可用于评价药物的体内效价和固有活性、剂型和给药方案的选择及优化等；在临床试验阶段则可用于估算给药剂量一浓度一效应或毒性之间的关系，以及年龄、性另q等对药效的影响等，从而满足新药开发和临床试验的要求。本文综述了近年来的药代动力学一药效学结合模型及其在药物研究开发领域中的应用。     

抗菌药物的药动学和药效学参数对临床用药的意义

目的:概述抗菌药物的药动学/药效学(PK/PD)参数与临床用药方案的关系.方法:参阅相关文献,综合、分析和归纳.结果:抗菌药物可分为浓度依赖性、时间依赖性且半衰期较短、时间依赖性且抗菌活性持续时间(PAE)较长者三类.结论:依据PK/PD综合参数对制定合理给药方案、提高临床疗效有重要意义.     

环维黄杨星D抗心肌缺血PK-PD结合模型的研究

摘 要 目的： 应用药动学 药效学（PK-PD）结合模型的研究方法考察环维黄杨星D（CVB-D）在心肌缺血家兔体内的药动学和药效学之间的关系。方法: 以冠状动脉结扎方法制备家兔心肌缺血模型,运用微透析采样技术考察CVB-D经皮给药和灌胃给药后在心肌组织内的浓度变化,分时采血检测试验动物血浆中乳酸脱氢酶(LDH)、肌酸激酶(CK)、丙二醛(MDA)活性变化,用药物学软件拟合PK-PD模型,并计算主要参数。结果: 药理效应与药物浓度之间符合抑制性S型最大效应模型,并准确计算出PK-PD结合模型参数。结论: 建立了环维黄杨星D在心肌缺血家兔体内的PK-PD结合模型,得到药动学和药效学参数,Cp-E曲线以及各个药效指标在不同给药途径条件下的量效方程。     

Optimizing therapy with antibacterial agents: use of pharmacokinetic-pharmacodynamic principles in pediatrics

The appropriate dosage of antibacterial agents is essential in achieving both clinical and microbiologic success in the treatment of infections in children. By using in vitro experimental data and animal model outcome data, the pharmacokinetic-pharmacodynamic (PK-PD) parameters predictive of antibacterial effect have been elucidated. For time-dependent drugs such as beta-lactams, the PK-PD parameter of interest is the percentage of time in a dosage interval for which drug concentrations remain above the minimum inhibitory concentration (MIC) of the infecting organism. For concentration-dependent drugs such as aminoglycosides, the PK-PD parameter of interest is the ratio of the area under the plasma concentration-time curve to the MIC. Recent studies using data on clinical and microbiologic outcomes from infected adults and children, combined with data on drug exposure, have confirmed the importance of these parameters and provided estimates of the PK-PD goals of therapy for various antibacterial agents. Application of these PK-PD principles allows rational dosage regimen selection, both for serious infections in critically ill children and for non-life-threatening community-acquired infections.     

厄贝沙坦在健康志愿者体内的药代动力学-药效学结合模型

目的研究厄贝沙坦在健康志愿者体内的药代动力学-药效学结合模型,探讨其临床药效学特征。方法18例健康志愿者厄贝沙坦片口服给药,测定血药浓度,同时测量收缩压(SBP)、舒张压(DBP)及心率(HR)等药效指标。计算厄贝沙坦的药动学参数,并根据sheiner效应室模型理论,计算药效学参数。结果厄贝沙坦的血药浓度时间曲线呈二室模型;厄贝沙坦抑制SBP和DBP的效应滞后于血药浓度,药效与血药浓度之间存在逆时针滞后环,药效和效应室浓度的关系符合SigmoidEmax模型。厄贝沙坦抑制SBP和DBP的药效学参数Emax分别为(14.8±1.5)和(9.8±2.1)mmHg,EC50分别为(0.29±0.11)和(0.18±0.07)mg·L-1,Keo分别为(0.62±0.09)和(0.68±0.07)h-1。结论建立了厄贝沙坦在健康者体内的药代动力学-药效学结合模型,有利于临床合理用药。     

Evidence of effectiveness: How much can we extrapolate from existing studies?

Drug development can be a science of extrapolation if the use of a drug exposure-response relationship is embraced and implemented through mechanistically oriented pharmacokinetic (PK)-pharmacodynamic (PD) modeling analysis and clinical trial simulation. The traditional requirement of at least 2 adequate and well-controlled phase III studies by the US Food and Drug Administration for drug approval can be waived in certain situations, substantially reducing the resources and time. In this article, the authors introduce a real drug development case where the chance for this exemption was maximized by actively using PK-PD modeling followed by clinical trial simulation, resulting in faster and more economical introduction of a new dosage regimen to patients.     

药物基因组学在临床药物治疗中的应用

经验性的药物治疗模式忽略了患者的个体差异,不能最大程度地发挥药物的疗效、规避毒副作用,导致各种不合理用药现象严重。近年来发展的药物基因组学通过关联患者个体的遗传物质与药物的药动学、药效学特性,可以帮助医师、药师预测药物疗效、估算药物剂量、调整给药方案以及预防药物不良反应发生,指导个体化合理用药。本文综述了药物基因组学在临床应用中的最新进展和突出问题,为其临床合理应用与推广提供借鉴。     

Pharmacokinetic/pharmacodynamic integration in drug development and dosage-regimen optimization for veterinary medicine

Pharmacokinetic (PK)/pharmacodynamic (PD) modeling is a scientific tool to help developers select a rational dosage regimen for confirmatory clinical testing. This article describes some of the limitations associated with traditional dose-titration designs (parallel and crossover designs) for determining an appropriate dosage regimen. It also explains how a PK/PD model integrates the PK model (describing the relationship between dose, systemic drug concentrations, and time) with the PD model (describing the relationship between systemic drug concentration and the effect vs time profile) and a statistical model (particularly, the intra- and interindividual variability of PK and/or PD origin). Of equal importance is the utility of these models for promoting rational drug selection on the basis of effectiveness and selectivity. PK/PD modeling can be executed using various approaches, such as direct versus indirect response models and parametric versus nonparametric models. PK/PD concepts can be applied to individual dose optimization. Examples of the application of PK/PD approaches in veterinary drug development are provided, with particular emphasis given to nonsteroidal anti-inflammatory drugs. The limits of PK/PD approaches include the development of appropriate models, the validity of surrogate endpoints, and the acceptance of these models in a regulatory environment.     

从剂型角度谈合理使用中成药

目的:通过探讨中药剂型与合理用药的关系,为临床合理使用中成药提供参考。方法:通过查阅文献,从剂型与疾病的关系、剂型与药效的关系、剂型与不良反应的关系以及中成药"同名异药"现象4个方面阐述中药剂型与合理用药的关系。结果与结论:剂型的合理选择是中药合理用药的一个方面,医药工作者必须引起重视。     

PK-PD modeling of irbesartan in healthy Chinese adult volunteers under non-steady-state conditions.

The purpose of this study was to construct a pharmacokinetic/pharmacodynamic model (PK-PD model) of irbesartan in healthy Chinese adult volunteers under non-steady-state conditions and provide relevant PK/PD parameters for use in clinical practice. Thirty-six healthy Chinese adult male volunteers received 150 or 300 mg irbesartan orally in tablet form (2 groups; n = 18 per group). Plasma concentrations were determined by HPLC and pharmacological effects, including effects on systolic (SBP) and diastolic blood pressure (DBP) were measured simultaneously. The experimental data were quantitatively analyzed according to the PK-PD model construct. PK/PD parameters were calculated. Blood pressure remained almost unchanged at an irbesartan dose of 150 mg under non-steady-state conditions. After a single dose of 300 mg, the pharmacokinetic profiles of irbesartan conformed to a two-compartment model. There were hysteresis loops between drug effects and plasma concentrations. The relationship between effects and effect compartment concentrations (Ce) could be represented by the sigmoid-Emax model. The Emax values for the inhibitory effects on SBP and DBP of irbesartan were 14.8 +/- 1.5 and 9.8 +/- 2.1 mmHg respectively, the EC50 values were 0.29 +/- 0.11 and 0.18 +/- 0.07 microg x ml(-1), while the K(eo) values were 0.62 +/- 0.09 and 0.68 +/- 0.07 h(-1), respectively. The PK-PD model of irbesartan was developed in healthy Chinese adult male volunteers, and may provide a more rational basis for dosage individualization.     

2007～2009年我院门诊不合格处方分析

目的：了解我院门诊处方存在的问题,提高处方质量,促进合理用药,减少药品不良反应。方法：对我院2007～2009年门诊处方按处方的规范性、用法用量、给药方案、药物配伍、重复用药等方面归类统计和分析评价。结果：门诊处方存在处方书写不规范、不合理用药问题。结论：应加强临床医生、药师对《处方管理办法》和药品说明书的学习,提高医生书写处方和合理用药的能力,提高药师审核处方的能力。     

我院门诊常见不合理用药处方分析

目的：保障患者用药安全，促进合理用药、方法：随机抽取我院2007年1～6月的门诊处方11539张，根据临床药理学知识砭文献资料，对不合理用药处方进行分类和统计，结果：不合理用药主要表现为给药方案不合理、重复用药、剂量不合理、溶媒选择不当、配伍不合理等。结论：将用药信息及时反馈给临床医师，可减少不合理用药，降低不良反应的发生。