药代动力学和药效动力学中数学建模与模拟的基本原理(2)

数学建模与模拟（modeling and simulation，M＆S）是药代动力学（药动学）与药效动力学（药效学）中重要的定量研究方法，在研究药物的处置和作用的机理、治疗药物监测及新药开发中发挥越来越重要的作用。但目前国内该领域的研究尚不多，有待大力发展。另外，M＆S涉及的数学知识较多，造成研究者阅读文献和实际应用的困难。本系列文章简要介绍M＆S的一些基本概念及重要原理，供读者参考。本部分着重讨论模型开发过程及拟合优度标准的有关问题。     

苦参碱及氧化苦参碱的药代动力学与药效动力学

以QTc延长率为效应指标,用药代动力学-药效动力学结合模型对苦参碱、氧化苦参碱iv后在免体内的处置和效应动力学作定量分析,两药的血浓时程均符合二房室模型,两药的效应与效应室浓度之间的关系均符合S形E_max模型。两药彼此的药动学和药效学性质均有明显差异,但它们各自的劳动学和药效学性质在所用剂量范围内均为非剂量依赖性。     

药代动力学药效动力学结合模型研究进展

药代动力学和药效动力学共同构成了现代药理学研究的基础。PK/PD模型是将两者相结合,以说明给予某一剂量后所引起的药理作用的时间过程。研究PK/PD关系不但有助于正确指导临床用药,还可以用于探讨药物作用机制、新药评估以及新制剂的开发等。本文就近些年来PK/PD模型在药理学和毒理学,临床应用以及新药开发等方面的研究进展作一简要的综述。     

药代动力学和药效动力学理论指导系统性抗真菌治疗

侵袭性真菌感染多见于有严重器官疾病、长期使用抗菌药物或免疫抑制人群,是住院患者常见的感染之一。目前,用于抗真菌治疗的药物数量较少,毒性较高。针对不同人群正确地进行抗真菌药物种类和剂量的选择非常重要。目前常用的抗真菌药物共有4类,它们是多烯类(两性霉素B)、唑类(氟康唑、伊曲康唑、伏立康唑)、嘧啶类(氟胞嘧啶)     

瑞格列奈在健康人体的药代动力学和药效动力学研究

目的：研究瑞格列奈的药代动力学和药效动力学。方法：19名健康男性受试者单剂量口服4 mg瑞格列奈片,采用HPLC-MS-MS法测定给药后不同时间瑞格列奈的血药浓度,用快速血糖仪测定不同时间指尖血的血糖。利用DAS 2.0计算药动学参数和进行统计分析。结果：瑞格列奈体内过程符合一室开放模型,达峰浓度Cmax为（83.1±23.6）μg/L;达峰时间tmax为（0.71±0.21）h;AUC0-8为（97.1±37.8）μg·L^-1.h;t1/2为（1.6±0.7）h。给药后血药浓度水平升高,血糖随之下降,于给药后1 h最低,达（3.0±0.65）mmol/L。结论：瑞格列奈起效迅速、作用持续时间短,适合餐后血糖调节,用于通过运动和控制饮食治疗无效的2型糖尿病患者。     

药代动力学-药效动力学结合模型在中药研究中的应用

药代动力学-药效动力学(Pharmacokinetic-pharmacodynamic,PK/PD)结合模型是研究中药体内代谢过程、药物效应及二者联系的有效工具,对于中药作用机制研究、临床用药优化有重要的参考价值。建立能体现中医药特色的PK/PD结合模型十分必要。该文针对目前PK/PD结合模型在中药研究领域的应用现状作了系统的阐述,并就中药效应物质基础的确定、效应指标的选择等关键问题进行探讨并提出建议,以期为今后的相关研究提供参考。     

氟卡胺的药代动力学与药效动力学

氟卡胺是抑制心脏传导间期AH,HV,QRS,QT的抗心律不齐新药。犬iv 2,4 mg/kg氟卡胺后呈二室型代谢动力学特点,其t_(1/2)为60～70min。健康人po 200 mg/kg与小鼠sc 10 mg/kg氟卡胺后呈一级吸收一室型,t_(1/2)为60～76 min。 以抑制传导间期为药效指标,犬iv 4 mg/kg氟卡胺后测各传导间期变化,计算药效动力学,公式为:△％=(△_(max)％)c~(-kt)。以血药浓度对数对相应时间传导间期变化(△％)作图呈线性相关,计算公式为:C=ae~b(△％)。     

蝙蝠葛碱在犬体内的药代动力学和药效动力学研究

目的　应用药动学药效学结合模型方法研究蝙蝠葛碱在犬体内的药代动力学和药效动力学之间的关系。方法　4只beagle犬给蝙蝠葛碱6mg·kg-1静脉注射后,分时取血及行心电、血压及血流动力学变化观察。采用反相高效液相紫外法测定血浆中蝙蝠葛碱的浓度。结果　蝙蝠葛碱主要药动学参数T1 /2α,T1 /2β,Vd,AUC分别为(0 049±0 016)h,(2 .7±0. 6)h, (15. 8±3 5)L·kg-1和(1. 48±0. 17)mg·h·L-1。对Q Tc的最大延长率为( 25 5±9 4 )%;SBP,DBP,±(dp/dt)max的最大抑制率分别为( 23 .0±4. 9 )%,(21 .9±5. 9)%, ( 42. 8±6 .6 )%和( 39 .0±17 .1 )%。药理效应滞后于血药浓度10 ~15min。药理效应与效应室浓度之间的关系符合sigmoid Emax模型。结论　建立了蝙蝠葛碱在犬体内血药浓度、时间、药物效应三者之间的关系。     

分析消癌平注射液的药代动力学及其药效分析

目的：使用LC-MS法来测定大鼠血浆里的17β-tenacigenin B以及tenacigenoside A的药代动力学和药效。方法色谱柱是AgilentZorbax SB-C18。预柱是 Agilent Zorbax SB-C18。流动相是甲醇-水（比例90∶10）。8只雄性的健康大鼠,分别对其尾静脉进行17β-tenacigenin B以及tenacigenoside A的注射。使用LC-MS来检测血浆里的成分的浓度。并且用DAS程序来拟合各不同成分药代的参数。结果17β-tenacigeninB以及tenacigenoside A不同的检测范围中线性关系良好（r≥0.996）。日内以及日间精密度RSD都不大于5.7%。大鼠尾静脉在注射消癌平之后,两个成分曲线都符合二室的模型。结论本文使用的方法简便可靠,可以测定大鼠血浆中的药物浓度。但是单体药代的参数,不能完全代表单体药代动力学的行为。     

药物临床试验计算机仿真简介

本文综述了药物临床试验计算机仿真的发展、设计及应用。从药代动力学、药效动力学的角度介绍了药物临床试验计算机仿真,进而根据国外药物临床试验的计算机仿真情况分析了仿真设计的基本方法以及模型计算和软件,最后讨论了药物临床试验计算机仿真的研究应用。     

蝙蝠葛苏林碱在犬体内药动学-药效学结合模型研究

目的 :研究蝙蝠葛苏林碱在beagle犬体内的药动学与药效学之间的关系。 方法 :4只beagle犬给予蝙蝠葛苏林碱 6mg·kg-1静脉注射后 ,分时取血 ,同时通过生理记录仪观察犬心电、血压及血流动力学的变化。采用反相高效液相色谱法测定血浆中蝙蝠葛苏林碱的浓度。结果 :蝙蝠葛苏林碱在犬体内动力学行为符合二房室开放模型 ,对犬药效学影响峰值为 10～ 15min ,皆明显滞后于血药浓度峰值。结论 :通过在beagle犬体内建立的蝙蝠葛苏林碱药动学 药效学 (PK PD)结合模型 ,可以成功预测蝙蝠葛苏林碱的血药浓度及其药理效应。     

蝙蝠葛苏林碱和蝙蝠葛碱在犬体内的药动学-药效学模型

目的：研究蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的药动学-药效学结合模型,并比较两种药物对其心电、血压和血流动力学的作用。方法：利用反相高效液相色谱法测定其血药浓度,生理记录仪观察药理效应,并计算药动学和药动学-药效学结合模型参数．结果：血药浓度-时间数据符合二房室开放模型．药效与效应室药物浓度之间的关系符合sigmoid-Emax模型．主要药动学和药动学-药效学结合模型参数在两种药物间差异无显著性．结论：蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的处置规律和对心血管系统的抑制作用基本-致。     

Pharmacokinetics/pharmacodynamics and the stages of drug development: Role of modeling and simulation

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation (M&S) are well-recognized powerful tools that enable effective implementation of the learn-and-confirm paradigm in drug development. The impact of PK/PD M&S on decision making and drug development risk management is dependent on the question being asked and on the availability and quality of data accessible at a particular stage of drug development. For instance, M&S methodologies can be used to capture uncertainty and use the expected variability in PK/PD data generated in preclinical species for projection of the plausible range of clinical dose; clinical trial simulation can be used to forecast the probability of achieving a target response in patients based on information obtained in early phases of development. Framing the right question and capturing the key assumptions are critical components of the "learn-and-confirm" paradigm in the drug development process and are essential to delivering high-value PK/PD M&S results. Selected works of PK/PD modeling and simulation from preclinical to phase III are presented as case examples in this article.     

Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications

Advancing age is characterized by impairment in the function of the many regulatory processes that provide functional integration between cells and organs. Therefore, there may be a failure to maintain homeostasis under conditions of physiological stress. The reduced homeostatic ability affects different regulatory systems in different subjects, thus explaining at least partly the increased interindividual variability occurring as people get older. Important pharmacokinetic and pharmacodynamic changes occur with advancing age. Pharmacokinetic changes include a reduction in renal and hepatic clearance and an increase in volume of distribution of lipid soluble drugs (hence prolongation of elimination half-life) whereas pharmacodynamic changes involve altered (usually increased) sensitivity to several classes of drugs such as anticoagulants, cardiovascular and psychotropic drugs. This review focuses on the main age-related physiological changes affecting different organ systems and their implications for pharmacokinetics and pharmacodynamics of drugs.     

Population Pharmacokinetic/Pharmacodynamic Modeling of Systemic Corticosteroid Inhibition of Whole Blood Lymphocytes: Modeling Interoccasion Pharmacodynamic Variability

Purpose To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model that characterizes the effects of major systemic corticosteroids on lymphocyte trafficking and responsiveness. Materials and Methods Single, presumably equivalent, doses of intravenous hydrocortisone (HC), dexamethasone (DEX), methylprednisolone (MPL), and oral prednisolone (PNL) were administered to five healthy male subjects in a five - way crossover, placebo - controlled study. Measurements included plasma drug and cortisol concentrations, total lymphocyte counts, and whole blood lymphocyte proliferation (WBLP). Population data analysis was performed using a Monte Carlo-Parametric Expectation Maximization algorithm. Results The final indirect, multi-component, mechanism-based model well captured the circadian rhythm exhibited in cortisol production and suppression, lymphocyte trafficking, and WBLP temporal profiles. In contrast to PK parameters, variability of drug concentrations producing 50% maximal immunosuppression (IC₅₀) were larger between subjects (73–118%). The individual log-transformed reciprocal posterior Bayesian estimates of IC₅₀ for ex vivo WBLP were highly correlated with those determined in vitro for the four drugs (r ²  = 0.928). Conclusions The immunosuppressive dynamics of the four corticosteroids was well described by the population PK/PD model with the incorporation of inter-occasion variability for several model components. This study provides improvements in modeling systemic corticosteroid effects and demonstrates greater variability of system and dynamic parameters compared to pharmacokinetics. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Receptor-mediated pharmacokinetic/pharmacodynamic model of interferon-beta 1a in humans

Purpose. An integrated receptor-based pharmacokinetic/pharmaco- dynamic (PK/PD) model of interferon- 1a (IFN- 1a) previously developed for monkeys was used to capture the time-course of drug and induced neopterin concentrations after intravenous (IV) and subcutaneous (SC) dosing in humans. Methods. Data were extracted from the literature by digitalization. Single-dose (3 IV doses and 1 SC dose) PK/PD profiles were simultaneously fitted using the basic model and the ADAPT II computer program. Additional submodels incorporating neutralizing antibody formation and negative feedback inhibition were applied to account for drug accumulation and lower than expected neopterin concentrations encountered after multiple-dosing (1 SC dose every 48 hs). Results. The basic model jointly-captured the nonlinear PK behavior of the drug and induced neopterin concentrations after all single doses. Slow and incomplete absorption (F = 0.33) of the SC dose resulted in prolonged drug concentrations reflective of flip-flop kinetics. Despite lower drug concentrations, SC dosing produced a similar neopterin profile as compared with the IV doses; however, with a longer time to peak effect and slightly higher neopterin concentrations at later time points. The PD component of the model represents a modified precursor-dependent indirect response model driven by the amount of internalized drug-receptor complex. The latter stimulated a 6-fold increase in the production of the neopterin precursor (S_max = 5.89). Drug accumulation and lower than expected neopterin concentrations after multiple dosing were also captured after the inclusion of the submodels. Conclusions. The present integrated PK/PD model for IFN- 1a is mechanistic in nature with receptor-mediated disposition and dynamics and was successfully applied to human clinical data.