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。     

Developing animal models of Zika virus infection for novel drug discovery

Introduction: Just before the Brazilian outbreak, Zika virus was related to a mild infection, causing fever and skin rash. Congenital Zika Syndrome was first described in Brazil, causing microcephaly and malformations in newborns. Three years after the outbreak, the mechanisms of Zika pathogenesis are still not completely elucidated. Moreover, as of today, there is still no approved vaccine that can be administered to the susceptible population. Considering the unmet clinical need, animal models represent an unprecedented opportunity to study Zika pathophysiology and test drugs for the treatment and prevention of vertical transmission.

Areas covered: The authors explore the current knowledge about Zika through animal models and advancements in drug discovery by highlighting drugs with the greatest potential to treat ZIKV infection and block vertical transmission.

Expert opinion: Some drugs used to treat other infections have been repurposed to treat Zika infection, reducing the cost and time for clinical application. One promising example is Sofosbuvir, which protected mice models against Zika pathogenesis by preventing vertical transmission. Importantly, there is a lack on exploration on the long-term effects of Zika Congenital Syndrome, as well as the possible ways to treat its sequelae.     

胆石病动物模型及药物靶点的研究进展*

胆石病是一种发生在胆囊和胆管的常见病、多发病,涉及一系列复杂的细胞及分子机制,如何制作和选择与人类胆石病相似的动物模型,不仅是深入研究胆石病发病机制的重要基础,也是筛选防治胆石病药物的有效手段。现概述目前常用的胆石病动物模型,并介绍胆石病药物靶点与治疗药物的研究进展。     

The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development

The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially.     

Simple animal models for amyotrophic lateral sclerosis drug discovery

ABSTRACT

Introduction: Simple animal models have enabled great progress in uncovering the disease mechanisms of amyotrophic lateral sclerosis (ALS) and are helping in the selection of therapeutic compounds through chemical genetic approaches.

Areas covered: Within this article, the authors provide a concise overview of simple model organisms, C. elegans, Drosophila and zebrafish, which have been employed to study ALS and discuss their value to ALS drug discovery. In particular, the authors focus on innovative chemical screens that have established simple organisms as important models for ALS drug discovery.

Expert opinion: There are several advantages of using simple animal model organisms to accelerate drug discovery for ALS. It is the authors’ particular belief that the amenability of simple animal models to various genetic manipulations, the availability of a wide range of transgenic strains for labelling motoneurons and other cell types, combined with live imaging and chemical screens should allow for new detailed studies elucidating early pathological processes in ALS and subsequent drug and target discovery.     

术后粘连防治药物的药效学动物模型制作与评价

根据腹部术后粘连防治药物的研究进展,将在药效学试验中粘连模型制作方法分为腹膜损伤、异物引入、局部缺血、多因素与子宫角粘连/盆腔粘连共5类;粘连程度的评价归纳为目视判断评分、粘连面积、粘连牵拉强度、病理切片、组织羟脯氨酸、细胞因子等9类指标.分析比较各种方法的优缺点,讨论如何建立标准的粘连模型与客观的评价方法.     

Modeling heart failure in animal models for novel drug discovery and development

Introduction: When investigating drugs that treat heart diseases, it is critical when choosing an animal model for the said model to produce data that is translatable to the human patient population, while keeping in mind the principles of reduction, refinement, and replacement of the animal model in the research.

Areas covered: In this review, the authors focus on mammalian models developed to study the impact of drug treatments on human heart failure. Furthermore, the authors address human patient variability and animal model invariability as well as the considerations that need to be made regarding choice of species. Finally, the authors discuss some of the most common models for the two most prominent human heart failure etiologies; increased load on the heart and myocardial ischemia.

Expert opinion: In the authors’ opinion, the data generated by drug studies is often heavily impacted by the choice of species and the physiologically relevant conditions under which the data are collected. Approaches that use multiple models and are not restricted to small rodents but involve some verification on larger mammals or on human myocardium, are needed to advance drug discovery for the very large patient population that suffers from heart failure.     

Gut microbiota modulates drug pharmacokinetics

Abstract

Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role in drug metabolism during enterohepatic circulation either before drug absorption or through various microbial enzymatic reactions in the gut. In addition, some drugs are metabolized by the intestinal microbiota to specific metabolites that cannot be formed in the liver. More importantly, metabolizing drugs through the gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding intestinal flora-mediated drug metabolism is critical to interpreting changes in drug pharmacokinetics. Here, we summarize the effects of gut microbiota on drug pharmacokinetics, and propose that the influence of intestinal flora on pharmacokinetics should be organically related to the therapeutic effects and side effects of drugs. More importantly, we could rationally perform the strategy of intestinal microflora-mediated metabolism to design drugs.     

双膦酸盐类药物的药动学及药物相互作用研究进展

双膦酸盐类药物用于预防与治疗骨吸收相关疾病,包括第1代的依替膦酸二钠、替鲁膦酸二钠、氯膦酸二钠,第2代的帕米膦酸二钠、阿仑膦酸钠,第3代的利塞膦酸钠、伊班膦酸钠、唑来膦酸等。该类药物口服达峰时间较短,吸收率偏低,生物利用度很低;骨结合部分的半衰期较长,药物留存时间也较长。与双膦酸盐联用产生相互作用的药物主要为：含有二价阳离子药物、其他双膦酸盐药物、华法林、苯妥英、非甾体类抗炎药、抗癌药、激素、H2受体拮抗剂以及肾毒性药物。从药动学角度解释双膦酸的药物相互作用,以避免不良反应发生。     

在药物动力学中立体选择性因素对药物相互作用的影响

综述了近几年对映体/对映体、对映体/片用药物在药动学中的相互作用.提出药动学相互作用研究中考虑立体选择性因素具有十分重要的临床意义,例如,避免相互作用引起的不良反应、增加治疗效果、理解血药浓度量效关系不一致现象以及提供研究生长点以进一步探求代谢处置机理等.应加强对立体选择性药动学相互作用的研究.     

群体药代动力学及其在新药研究中的应用

近年来新药临床研究越来越重视群体药代动力学的应用。群体药代动力学可以定量地描述病理、生理、合并用药等多种因素对药物代谢的影响，可将PK参数中的各种变异区分开，指导用药方案的调整，从而增强对新药有效性和安全性的评价。本文对群体药代动力学的研究方法及其在新药研究中的应用进行综述．     

脑胶质瘤治疗及其动物模型的研究进展

脑胶质瘤是原发性中枢神经细胞肿瘤中最常见并且死亡率最高的肿瘤。尽管对其研究的重视程度日渐增加,胶质瘤依然是现今最难治疗的肿瘤。许多候选药物在临床前试验有较好效果的药物在临床试验后期失败,提示动物模型的改进的必要性。随着药理学,药剂学与分子生物学研究的进展,建立科学的、可重复性好的动物模型对于胶质瘤的发病机制,评价药物疗效与给药方式有非常重要的意义。本文将目前对胶质瘤的治疗方法与动物模型的研究进行综述。     

Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development

Over the past few decades, monoclonal antibodies (mAbs) have become one of the most important and fastest growing classes of therapeutic molecules, with applications in a wide variety of disease areas. As such, understanding of the determinants of mAb pharmacokinetic (PK) processes (absorption, distribution, metabolism, and elimination) is crucial in developing safe and efficacious therapeutics. In the present review, we discuss the use of physiologically-based pharmacokinetic (PBPK) models as an approach to characterize the in vivo behavior of mAbs, in the context of the key PK processes that should be considered in these models. Additionally, we discuss current and potential future applications of PBPK in the drug discovery and development timeline for mAbs, spanning from identification of potential target molecules to prediction of potential drug-drug interactions. Finally, we conclude with a discussion of currently available PBPK models for mAbs that could be implemented in the drug development process.     

药物动力学和药效动力学结合在抗菌药物研发和临床治疗中的应用

面临耐药性致病菌的逐年增加,新型抗菌药物亟待开发。众所周知,新药开发是一个艰难和复杂的过程。制定合理给药方案是药物开发的重要课题,而以制定抗菌药物的合理给药方案最富挑战性。近二十年来,便宜快捷的体外动力学实验和动物体内感染模型以及药效学数据处理方法不断完善,其价值在抗菌新药开发上被不断验证和肯定,弥补了临床试验所无法获得的信息。近十年来临床群体药代动力学模型和蒙地卡罗模拟结合临床前实验确定的靶值,致病菌MIC分布,利用电脑模拟比较不同给药方案的中靶率,已成为临床三期试验确定最佳给药方案行之有效的方法和针对耐药菌抗菌药物临床剂量再评价和进一步调整的科学依据。可以预期,在今后的抗菌素新药的开发上,人们将更有把握从临床前的实验数据来预计临床最佳给药方案,并优化临床试验的设计,达到既快速又经济的目的。     

Continuous transepidermal drug collection: Basis for use in assessing drug intake and pharmacokinetics

Continuous transepidermal drug collection (CTDC) has been proposed for use in assessing ethanol intake and in monitoring compliance with therapeutic regimens. Exploration of a theoretical basis for use of CTDC in these circumstances and for its use in assessing other aspects of drug disposition kinetics was undertaken. Effects of single and multicompartmental drug disposition models, single dose and multiple dose regimens, with regular and irregular doses and dosing intervals, and zero-order, first-order, and Michaelis-Menten excretion patterns were explored. First-order transepidermal drug transfer was assumed with and without back transfer from the collection device. These analyses suggest that the utility of CTDC is severely restricted when back transfer from the collection device is substantial. With back transfer minimized, CTDC may be a useful tool for assessing amount of drug exposure, compliance with therapeutic regimens, and relative bioavailability, but offers little advantage over discrete sampling of other body fluids in the study of other aspects of drug disposition kinetics.The views of the authors do not purport to reflect the positions of the Department of the Army or the Department of Defense. (Para. 4-3, AR 360-5).     

药物转运体和代谢酶在抗生素药动学中的作用

近年来,对体内药物转运体的研究取得了重大进展,越来越多的转运体被发现及研究,其对药物的跨膜转运,具有重要的意义。各种转运体包括摄取转运体和外排转运体对药物的体内过程以及药物相互作用均有着重要影响。研究表明大多数抗生素的体内过程都与转运体和代谢酶有关,因此,归纳总结了转运体和代谢酶在抗生素的药动学和药物相互作用中的最新研究进展,为临床合理用药提供参考。     

新药发现阶段药物毒理学研究的策略与方法

随着重大创新药物创制专项的实施,我国创新药物研发的数量将步入稳定上升期。纵观整个药物研发流程,从药物发现、临床前研究、临床研究直到药物上市,药物毒理学研究贯穿始终,并起着非常重要的作用。鉴于创新药物发现阶段药物毒理学地位和作用的日益突出,文中就相关研究的策略与方法作简要阐述。