生物标志物在药品生命周期中的应用与相关法规

生物标志物（biomarker）是一种能客观测量并评价正常生物过程、病理过程或对药物干预反应的指示物，可有效提高新药研究开发决策，指导候选药物早期临床试验，降低新药研发失败的风险。其在新药开发与临床治疗中的关键作用受到世界各国（地区）的关注，纷纷出台相应的支持政策。本文通过对生物标志物的定义与分类、各国对生物标志物在药品研究开发中应用的政策法规以及生物标志物分析检测技术规范等进行分析和综述，提出和制订《药物生物标志物分析检测验证技术指导原则》（草案），提交国家药典委员会，以期为生物标志物的发现、检测、验证及其在医药行业的应用提供技术指导。     

毒理基因组学在生物标志物研究中的应用

近年来,毒理基因组学的快速发展为生物标志物的研究提供了一个更广阔的空间。生物标志物作为一种可以客观衡量和评价正常生理、病理过程及治疗药物药理学效应的指标,如今已被广泛应用于临床诊断和新药开发等多个领域。就毒理基因组学在发现和筛选生物标志物方面的研究现状和进展进行综述。     

分子影像技术在抗肿瘤药物研发中的应用进展

目的:为借助分子影像技术提高抗肿瘤药物研发效率、降低研发成本提供参考。方法:以"分子影像技术""药物研发""肿瘤诊断""生物标志物"等为关键词,通过检索和筛选中国知网、中国国家图书馆、PubMed、Web of Science等数据库收录的2017年4月以前发表的分子影像技术用于抗肿瘤药物研发的最新文献,进行整理、归纳和综述。结果与结论:近年来分子影像技术已取得重大进展,正越来越广泛地应用于抗肿瘤药物研发,并在药物生物分布标志物(药物由血液循环运送到体内各脏器的过程)、药效学生物标志物(药物对机体的作用及作用机制)、疾病生物标志物(用于疾病诊断、判断疾病分期或者用来评价新药或新疗法在目标人群中的安全性及有效性)及患者选择生物标志物(识别可能对治疗有反应的患者,指导治疗)等方面发挥重要作用。分子影像技术的成功应用,有望提高抗肿瘤药物开发全链条的效率和收益,其潜在价值有待进一步开发。     

基于药物基因组学的药物流行病学研究设计概述

摘要：药物基因组学在新药临床试验及个体化用药中发挥着重要作用。基因组水平的生物标志物可用在药物流行病学研究的设计中,用于识别个体对药物疗效有差异的原因,以及有药物毒性风险的个体。本文介绍了药物基因组学生物标志物的筛选方法,以及举例介绍了如何用药物流行病学的方法开展药物基因组学研究,包括临床随机对照试验和观察性研究。     

寡核苷酸药物及生物标志物的生物分析研究进展

寡核苷酸已成为多种疾病诊断和治疗的候选药物。寡核苷酸药物及其代谢物、生物标志物的定性定量分析是药物开发和评估所必需的,良好的分析方法有利于控制药品质量及准确定量药品浓度。本文主要探讨了逆转录-实时荧光定量PCR (RT-qPCR)、液相色谱-荧光(LC-FL)、液相色谱-质谱联用（LC-MS/MS）、液相色谱-高分辨质谱联用（LC-HRMS）在寡核苷酸药物和生物标志物的应用及各自的优缺点,旨在概述目前现有寡核苷酸药物和生物标志物的生物分析方法,以期为从事寡核苷酸诊断和治疗药物的研发、分析人员及企业提供参考,以期提高此类新药或仿制药一致性评价分析的水平。     

CYP3A酶内源性标志物的研究进展

CYP3A酶主要分布于人体肝脏和小肠,广泛参与各种药物代谢。该酶在介导药物代谢的同时也会受底物影响,其活性被诱导或抑制,从而影响其他经由CYP3A酶代谢的药物体内过程。目前可以通过体外探针药物和内源性生物标志物评价CYP3A酶活性,前者需要口服探针药物,后者只需检测内源性标志物如4β-羟基胆固醇和6β-羟基氢化可的松。文献报道,研究CYP3A酶活性除了有助于阐明不同个体的药物代谢差异,还可以提示药物相互作用情况下合用药物的剂量调整,预测药物疗效和毒性反应,为个体化用药提供理论指导,评估新药潜在的药物相互作用,降低新药上市风险。笔者对上述2种常用的内源性标志物的相关研究和临床应用进行综述。     

蛋白质组学技术在药物性肝损伤生物标志物研究中的应用

临床前药物性肝损伤的评价存在灵敏性低和特异性差的问题,常产生假阴性结果和出现意外的毒性,是导致药物终止开发甚至退市的重要原因之一。在药物肝毒性临床前研究中,可以利用蛋白质组学技术的快速、灵敏、高通量等优点,寻找和发现新的肝毒性生物标志物,使药物开发过程更为安全有效。本文对肝毒性生物标志物的研究现状,蛋白质组学在生物标志物的发现及验证等方面的技术发展进行了综述分析,并且着重归纳了该技术在中药致肝损伤方面的生物标志物研究中的应用。与传统评价方法相比,蛋白质组学技术对于发现新型肝潜在毒性生物标志物具有不可替代的优势。随着蛋白质组学技术结合其他组学技术的发展,其在药物肝毒性早期筛选、生物标志物的临床桥接等方面将取得突破性的进展。     

肝毒性生物标志物研究进展

药物肝毒性是医药界关注的重要问题。及时准确地评价药物的肝毒性,寻找特异性强、灵敏度高的肝毒性生物标志物对新药研发及保证临床用药安全具有重要意义。针对传统的肝毒性生物标志物（包括谷氨酸氨基转移酶、天冬氨酸氨基转移酶、谷氨酸脱氢酶等）,以及新发现的生物标志物（血清F蛋白、嘌呤核苷磷酸酶、激肽原对氧磷酶）进行综述,为药物肝毒性的研究及防治提供参考。     

MicroRNA对药物转运蛋白和代谢酶中的调控研究

微小RNA（miRNA）是一类内源性长18～25个核苷酸的非编码小RNA分子,在进化过程中具有高度保守性,在转录后水平调控基因的表达,从而在生物过程中发挥重要的作用。生物信息学分析表明人类全部基因的1/3都受到miRNA的调控。目前的研究表明,miRNA广泛调控机体各种生理和病理过程,可能是药物个体差异的原因,在将来可作为个体化给药分子标志物或指导新药开发。     

转运体生物标志物的研究进展

药物转运体介导着药物的吸收、分布及消除等过程,其广泛的底物专属性是产生药物相互作用的主要因素之一。生物标志物作为转运体的底物,能通过自身浓度的变化反映转运体蛋白的功能,具有重要的药理学意义。对生物标志物的研究有助于揭示转运体介导的药物相互作用。本文综述了具有一定代表性的肝肾转运体生物标志物,并讨论了生物标志物在预测转运体参与的药物相互作用过程中的意义、局限性和未来方向。     

Promises of biomarkers in drug development--a reality check

Biomarkers have been a buzz word in drug development for the last 5 years. But where do we stand now? This perspective article will demonstrate to which extent biomarkers have impacted drug development and the use of drugs. In particular, the different types of biomarkers, their identification, validation and use in different phases of drug development from drug discovery, to approval, to clinical application will be discussed as well as the state‐of‐the‐art biomarker technologies and promising future methods. The high interest in biomarkers has generated the need for development of new technologies and refinement of existing ones. Besides discussing their perspectives of applications, the present article also illustrates the future of biomarker development in terms of qualification for regulatory use and co‐development.     

Metabolomic approaches in the discovery of potential urinary biomarkers of drug-induced liver injury (DILI)

Drug-induced liver injury (DILI) is a major safety issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market. The identification of DILI biomarkers is a labor-intensive area. Conventional biomarkers are not specific and often only appear at significant levels when liver damage is substantial. Therefore, new biomarkers for early identification of hepatotoxicity during the drug discovery process are needed, thus resulting in lower development costs and safer drugs. In this sense, metabolomics has been increasingly playing an important role in the discovery of biomarkers of liver damage, although the characterization of the mechanisms of toxicity induced by xenobiotics remains a huge challenge. These new-generation biomarkers will offer obvious benefits for the pharmaceutical industry, regulatory agencies, as well as a personalized clinical follow-up of patients, upon validation and translation into clinical practice or approval for routine use. This review describes the current status of the metabolomics applied to the early diagnosis and prognosis of DILI and in the discovery of new potential urinary biomarkers of liver injury.     

Biomarkers in drug discovery and development: from target identification through drug marketing

Biomarkers of disease play an important role in medicine and have begun to assume a greater role in drug discovery and development. The challenge for biomarkers is to allow earlier, more robust drug safety and efficacy measurements. Their role in drug development will continue to grow for the foreseeable future. For biomarkers to assume their rightful role, greater understanding of the mechanism of disease progression and therapeutic intervention is needed. In addition, greater understanding of the requirements for biomarker selection and validation, biomarker assay method validation and application, and clinical endpoint validation and application is needed. Biomarkers need to be taken into account while the therapeutic target is still being identified and the concept is being formulated. Biomarkers need to be incorporated into a continuous cycle that takes what is learned from the discovery and development of one series of biomarkers and translates it into the next series of biomarkers. Optimum biomarker development and application will require a team approach because of the multifaceted nature of biomarker selection, validation, and application, using such techniques as pharmacoepidemiology, pharmacogenetics, pharmacogenomics, and functional proteomics; bioanalytical method development and validation; disease process and therapeutic intervention assessments; and pharmacokinetic/pharmacodynamic modeling and simulation to improve and refine drug development. The potential for biomarkers in medicine and drug development will be limited by the least effective component of the processes. The team approach will minimize the potential for the least effective component to be fatal to the rest of the process. As scientific/regulatory foundations for biomarkers in medicine and drug development begin to be established, successes and applications will need to be effectively communicated with all of the stakeholders, including not only internal and external drug developers and regulators but also the medical community, to ensure that biomarkers are totally integrated into drug discovery and development as well as the practice of medicine.     

生物标志物在药物性肝损伤中应用的研究进展

摘 要药物性肝损伤是伴随着药物使用而出现的最常见不良反应之一,也是药物研发失败及药物撤市或限制使用的主要原因。生物标志物检测是临床前药物肝毒性评价和临床患者潜在肝损伤诊断的重要技术手段,而传统的肝损伤指标因缺乏特异性和灵敏性等因素,限制了其在早期评价中的应用。因此,寻求及验证新的生物标志物势在必行。本文主要对结合现代组学等技术探索出具有科研及临床价值的新型生物标志物研究现状予以概述。以期为科研人员、临床医师、新药研发机构等预测药物的肝毒性及可能的发展趋势,判断药物引起的肝损伤程度等提供参考。     

Method Validation and Measurement of Biomarkers in Nonclinical and Clinical Samples in Drug Development: A Conference Report

No Heading Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics. Biomarkers can improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Early implementation of biomarker strategies thus promises to reduce costs and time-to-market as drugs proceed through increasingly costly and complex clinical development programs. The 2003 American Association of Pharmaceutical Sciences/Clinical Ligand Assay Society Biomarkers Workshop (Salt Lake City, UT, USA, October 24–25, 2003) addressed key issues in biomarker research, with an emphasis on the validation and implementation of biochemical biomarker assays, covering from preclinical discovery of efficacy and toxicity biomarkers through clinical and postmarketing implementation. This summary report of the workshop focuses on the major issues discussed during presentations and open forums and noted consensus achieved among the participants on topics from nomenclature to best practices. For example, it was agreed that because reliable and accurate data provide the basis for sound decision making, biomarker assays must be validated in a manner that enables the creation of such data. The nature of biomarker measurements often precludes direct application of regulatory guidelines established for clinical diagnostics or drug bioanalysis, and future guidance on biomarker assay validation should therefore be adaptable enough that validation criteria do not stifle creative biomarker solutions.     

Biomarkers of drug-induced adverse events

Many drugs on the market have the potential to cause undesirable side effects. Biomarkers used today, at best, diagnose an existing injury, such as cell death or abnormal functioning of an organ. More valuable would be biomarkers that could be used to prevent a patient from receiving an inappropriate drug or to identify very early signs of injury so the offending drug may be discontinued prior to overt tissue injury. Biomarkers currently used to identify drug-induced injury to the liver, heart and kidney will be discussed, as will some newer biomarkers. Progress on finding new biomarkers through the use of pharmacogenetics and pharmacogenomic approaches, consortia that may assist in their discovery and qualification for use, regulatory issues and the pharmacoeconomic considerations that may drive or hinder such new tests are also described.     

FDA和EMEA批准7种肾损伤生物标志物正式使用

药物安全性预测联盟（PSTC）集合众多制药企业的力量,在美国食品药品监督局（FDA）和欧洲医药评价署（EMEA）的指导下致力于药物安全性监测的研究,并向FDA和EMEA呈交了7种肾损伤生物标志物的研究结果。目前,FDA和EMEA评估并接受了这7种新的生物标志物,使之用于检测尿中反映肾损伤的信号。这些新的检测指标现在可作为药物评价的一部分,用于实验室探索实验性药物的安全性,从而使药物在安全性上更加可靠。     

2020年首创性小分子药物研究实例浅析

随着我国对创新药物研发的重视与投入,首创性(first-in-class)药物的研发逐渐成为各大药企和科研机构争相追求的目标.首创性药物的研制需要深厚的基础研究积累、大量的资金投入和创新的研究方法,往往是新药研究中的风向标.2020年,美国食品药品监督管理局(FDA)共批准上市了53个全新药物,小分子药物依旧以38项获...     

美国新药上市后定期汇总报告的研究

周期性药物不良事件报告和药品年度报告是美国新药上市后的美国食品药品监督管理局要求药企递交的两种主要的定期汇总报告。这两种报告为管理上市药品、评估药品风险利益提供了必要的信息。文章介绍了两种报告的汇报时限和内容,并将这两种报告与中国采用的定期安全性更新报告进行了比较,指出不同。最后阐述了定期汇总报告在未来的变化趋势,希望对国内该领域工作起到参考借鉴作用。