抗体药物的药学监护

近年来，抗体药物在自身免疫性疾病及肿瘤治疗领域表现非凡，成为当前药物研发的热点之一。与传统小分子药物相比，抗体药物具有结构功能复杂、药动学特殊及免疫原性等特点，使其对临床合理用药提出了新的挑战。本文以抗体药物的结构和药动学特征为基础，从抗体药物的有效性、安全性、经济性、免疫原性和药物警戒五个方面，阐述如何将药学监护手段应用于抗体药物，旨在为抗体药物的临床合理使用提供参考。     

单克隆抗体药物药代动力学特征、分析方法以及体内分析方法学研究进展

近年来,单克隆抗体药物发展迅速,在肿瘤、免疫、血液等系统疾病领域应用日益广泛。截至2019年其全球处方药物市场占比已达15.3%(1400亿美元)。单克隆抗体药物作为一种大分子蛋白,因其特殊的结构和生理性质,在体内的吸收、分布、代谢及排泄均与小分子药物存在较大差异,具有靶点介导的药物处置、非线性药动学代谢、时间依赖性、较长的半衰期等独特的药代动力学特征,充分了解这些特征有益于该类药物分析方法的开发。单克隆抗体药物在生物体内的处置具有特殊性和复杂性,极大地增加了生物检测的难度,因此必须建立专属、灵敏、准确、可重复的测定分析方法。本文旨在论述单克隆抗体药物的药代动力学特征、常用分析方法及其优缺点、体内分析方法学验证要求等,并逐点与小分子药物进行对比讨论,以期为单克隆抗体药物的分析技术开发提供部分参考。     

生物技术药物的药动学特点及研究方法

生物技术是利用生物体或其组成成分发展产品的技术体系。采用生物技术研制和开发的药物称为生物技术药物。生物技术药物不同于传统的化学药物。为了进一步了解生物技术药物自身的特点及其药动学的研究方法,现综述如下。     

治疗性蛋白药物的药动学和药效学评价

治疗性蛋白药物是一类用于治疗的高分子物质(>1kDa)可分为多肽和基因工程药物、单克隆抗体和基因工程抗体、重组疫苗等。与小分子药物相比,其具有高活性、特异性强、低毒性、生物功能明确、有利于临床应用的特点。由于其成本低、成功率高、安全可靠,故已成为医药产品中的重要组成部分。同时,由于该类药物为外源性蛋白,具有稳定性不高、分子量大以及物理化学性质与小分子药物不同等特点,其药动学和药效学研究面临许多困难。本文从药动学和药效学两个方面,综述治疗性蛋白药物的影响因素和研究方法。1治疗性蛋白药物的药动学1.1吸收由于蛋白质…     

生理药动学模型的研究与应用进展

摘要：生理药动学(PBPK)模型可以利用临床前数据预测药物在人体内的药动学行为,还可以探讨各种生理参数,如年龄、种族或疾病状况对人体药动学的影响,从而指导用药剂量和给药方案,进行药物相互作用的风险评估。本文简要介绍了PBPK模型的概念、建模方法和常用软件,以及在指导新药研发、毒理学和风险评估、评价药物-药物相互作用、药品监管领域等方面的应用进展,以期了解候选药物的药代动力学,为提高药物研发效率提供方法。     

治疗类风湿性关节炎的选择性 Janus 激酶3抑制药peficitinib

摘 要Peficitinib是日本安斯泰来制药公司开发的口服小分子选择性Janus激酶3抑制药,于2019年3月在日本获准用于治疗对传统药物反应不佳的类风湿性关节炎成年患者。本文主要描述该药的药效学、药动学、临床疗效和安全性等信息,旨在为临床医生和患者提供参考。     

药动学研究常用软件介绍

药动学是一门研究药物体内动态变化规律及其影响因素的学科。药动学模型研究从经典的房室模型,统计矩理论的应用,到复杂的群体药动学、生理药动学以及药动-药效学建模,都需要可靠的软件工具来完成复杂的数学计算过程。一些商业公司开发的药动学模型专业软件,已在药物研发和科学研究中广为应用;另一方面,开源工具正得到大力推广。本文总结目前用于药动学模型研究的主流软件工具,对其功能应用做简要介绍,以期为国内相关研究者提供有价值的信息。     

单克隆抗体药物及抗体偶联药物的药代动力学研究进展

近几年来,随着国际上一些重磅生物药专利的到期或即将到期,以及以PD-1、PD-L1等免疫检查点为靶标的单克隆抗体药物的上市和其在肿瘤治疗方面显示的疗效,在国内引发了抗体药物的仿制以及研发热潮。与传统小分子药物的药代动力学特征不同,抗体类药物的药物代谢动力学特征有着其特有的规律。本文从药代动力学特征的四个方面：吸收（Absorption）、分布（Distribution）、代谢（Metabolism）、排泄（Excretion）,对单克隆抗体药物以及抗体偶联药物（Antibody-Drug Conjugates, ADC）的药代动力学特征进行综述。     

创新生物医药研发的再思考

21世纪是生物科学的世纪,是生物技术、生物信息学和纳米技术的时代.生物技术、生物信息学和纳米技术为生物医药的发展提供了前所未有的机遇,带来迎接创新挑战的科学基础和力量,理应对传统创新药物研发模式带来革命性变化.回顾半个多世纪的传统创新药物研发模式,不难发现世界高成本、高风险、低效率的研发传统模式,存在不利于创新发展的问题.根据近20年的进展和研发水平,估计未来10年小分子化学药物的创新仍然主导世界新药发展,小公司的前景和多渠道整合研发是世界新药不可抗拒的力量.面对挑战,采用先进监管科学技术和新方法,加强生物技术新药的研究开发和药物有效性和安全性风险评估研究十分迫切.其次,创新药物的高成本、高风险、低效率瓶颈需要提升合作效率来突破.第三,根据我国国情,注意发展分子靶向药物的研发战略和策略,重视给药系统的研究、明确创仿结合发展新药的目标,更需要合理整合研发发展模式,需要优化资源配置来提高研发效益.第四,中国特色的自主创新需要国家政策引导,政府在规划、政策、开放和实力建设的四大举措的实现,需要企业实力支持和官-产-学-研-企的多元协同创新体制的变革.     

单克隆抗体颗粒表征的现状与挑战

随着生物技术的快速发展,治疗性单克隆抗体已成为生物技术药物中增长最快速的部分,也成为临床医疗的重要组成部分,并不断为患者提供创新的治疗选择.单克隆抗体中的颗粒物是影响药物安全性和有效性的重要因素.本文论述了近年来单克隆抗体药物药典监测要求、重要的检测技术及各自应用范围、在药物研发不同阶段的监测考虑及对颗粒进行全面表征与...     

抗体药物的药物代谢动力学特点及研究进展

抗体药物是一种可与相应抗原发生特异性结合的免疫球蛋白。该研究从抗体药物的结构入手，对抗体药物的药物代谢动力学基本特点进行综述，并着重介绍了其不同于小分子药物的独特代谢特征，主要包括与靶点介导的药物处置、新生儿 Fc受体介导的循环再利用、糖基化修饰和电荷异质性对清除速率的影响以及与抗药物抗体相结合导致清除加快。最后总结了纳米抗体、双特异性抗体、抗体药物偶联物等新型抗体药物的药物代谢动力学研究进展。     

抗肿瘤药物在伴第三间隙积液患者中的药动学研究进展

第三间隙积液(third space fluid,TSF)是晚期恶性肿瘤常见的并发症之一,主要包括恶性胸腔积液、恶性腹腔积液等。TSF是影响抗肿瘤药物药动学(pharmacokinetics,PK)的潜在因素。药物可经体循环分布于TSF,对TSF产生治疗作用;可能导致血药浓度减少,或可降低全身抗肿瘤疗效;若在TSF中蓄积则可能引发毒性反应。本文综述抗肿瘤药物在恶性肿瘤伴TSF患者中的PK研究进展,总结药物在血液和TSF中的PK特征,以期为患者安全、有效地应用抗肿瘤药物提供参考。     

Indole-2-carboxamide derivatives: a patent evaluation of WO2015036412A1

Introduction: Hippocampal neurogenesis in adults is a new and attractive target for the treatment and prevention of neurodegenerative and neuro-psychiatric diseases. Recently, neurogenesis stimulating activity was observed in some of the commonly used small molecule drugs such as antidepressants and atypical antipsychotics. Stimulation of neurogenesis is attractive mainly due to its wide scope of application, ranging from depressions, schizophrenia, dementia, Parkinson`s and Alzheimer`s Disease to various brain injuries.

Areas covered: New compounds based on 7-phenyl or 7-pyridinyl-1H-indole-2-carboxamide showed interesting neural stem cell proliferation inducing activity in vitro and were claimed as potential therapeutics for various neurodegenerative and neuropsychiatric diseases as well as brain injuries. The potential of the presented compounds is evaluated with respect to other small molecule neurogenesis inducers in literature.

Expert opinion: Nanomolar in vitro activities of presented compounds and their favorable physico-chemical properties, giving a fair chance of good oral bioavailability and sufficient CNS penetration, make these compounds promising drug candidates. The biggest drawback of the presented application is the absence of pharmacokinetics, toxicity and in vivo activity data. On the other hand, the high number of applications in this area (seven published in last two years) indicates that Hoffmann-La Roche takes it seriously.     

Research and development in drug innovation: reflections from the 2013 bioeconomy conference in China,lessons learned and future perspectives

The enormous progress biotechnology, bioinformatics and nanotechnology made in recent years provides opportunities and scientific framework for development of biomedicine and constitutes a paradigm shift in pharmaceutical R&D and drug innovation. By analyzing the data and related information at R&D level over the past decades, developmental tendency and R&D patterns were summarized. We found that a growing number of biologics in the pipeline of pharma companies with successful products already in the market though, small molecular entities have primarily dominated drug innovation. Additionally, small/medium size companies will continue to play a key role in the development of small molecule drugs and biologics in a multi-channel integrated process. More importantly, modern and effective R&D strategies in biomedicine development to predict and evaluate efficacy and/or safety of 21st century therapeutics are urgently needed. To face new challenges, developmental strategies were proposed, in terms of molecular targeted medicine, generic drugs, new drug delivery system and protein-based drugs. Under the current circumstances, interdisciplinary cooperation mode and policy related to drug innovation in China were deeply discussed as well.KEY WORDS: Bioeconomy, Biomedicine, Drug development, Innovation, Research and development, Strategy and models     

The interactions of anti-cancer drugs approved in the last decade in the United States with membrane transporters

Membrane transporters play a role in determining the absorption, distribution, metabolism and excretion of small molecule anticancer drugs and mediating chemosensitivity and resistance of tumor cells to these drugs. Our understanding of the influence of these transporters on the pharmacokinetics, clinical effectiveness and tolerability has considerably increased in the last decade. Therefore, determining the interaction of membrane transporters with small molecule anticancer drugs can facilitate the development of effective and safe treatments. We reviewed the interaction of the small molecule anticancer drugs approved in the last decade with the more common membranes transporters, such as ABCB1, ABCG2, and OATP. The drugs were divided into three categories: targeted therapies, cytotoxic agents and hormonal therapies. The literature appears to focus on the interaction of the targeted therapies compared to the remaining two categories. Furthermore, most data stemmed from nonclinical studies with only a few clinical examples where transporters corresponded with systemic exposure or clinical effectiveness or tolerability. More nonclinical and clinical studies are needed to improve the ability to use the findings from these nonclinical studies to predict clinical outcomes, but the literature appears to be rapidly expanding as our understanding of these transporters groups. Therefore, determining the interaction of membrane transporters with small molecule anticancer drugs can be facilitate the development of effective and safe treatment.     

基于生物信息学方法探究白癜风铁死亡相关发病机制和潜在治疗药物筛选

目的 通过生物信息学方法 分析白癜风疾病中铁死亡基因及相关发病机制,并筛选通过铁死亡相关途径治疗白癜风的潜在药物。方法 从FerrDB数据库获取铁死亡基因,通过R分析数据集GSE53146中差异表达基因,随后二者取交集。通过SVM-REF算法和LASSO回归构建机器学习模型预测白癜风铁死亡关键基因并通过数据集GSE75819进行基因表达验证。GSE203262单细胞数据进行细胞聚类分析,发现与关键基因高度相关且参与白癜风发病的关键细胞群,随后通过HPA数据库对基因表达细胞进行验证。利用cAMP数据库筛选关键基因相关小分子药物,利用分子对接技术验证小分子化合物与基因结合的能力。最后进行单基因免疫细胞相关性分析及GSEA-KEGG分析探讨小分子药物治疗白癜风的相关免疫机制。结果 获得458个铁死亡基因和706个差异表达基因,二者交集基因23个。机器学习预测模型筛选出RRM2、LCN2、OTUB1、SNCA、CTSB、WWTR1作为关键基因。外部数据集验证、单细胞聚类和HPA数据均提示关键基因中OTUB1、CTSB和LCN2主要在角质形成细胞、黑素细胞和朗格汉斯细胞等重要皮肤细胞中表达。通过...     

Progress in the research of artemisinin-related antimalarials: An update

Artemisinin, a sesquiterpene lactone endoperoxide isolated fromArtemisia annua L., and a number of its semisynthetic derivatives have shown to possess antimalarial properties. They are all eflective againstPlasmodium parasites that are resistant to the newest and commonly used antimalarial drugs. This article gives a survey of the literature dealing with artemisinin-relaled antimalarial issues that have appeared from the end of 1989 up to the beginning of 1994. A broad range of medical and pharmaceutical disciplines is covered, including phytochemical aspects like the selection of high-producing plants, analytical procedures, and plant biotechnology. Furthermore, the organic synthesis of artemisinin derivatives is discussed, as well as their mechanism of action and antimalarial activity, metabolism and pharmacokinetics, clinical studies, sideeffects and toxicology, and biological activities other than antimalarial activity.     

抗体偶联药物的分子特点及其药代动力学研究考虑

随着我国药物研发和临床试验水平的不断提高,近年来抗体偶联药物(Antibody-Drug Conjugate, ADC)的相关研究和注册申报也正在增多。ADC类药物由抗体、连接子和小分子毒素组成,在兼具高度靶向性和高细胞毒性优势的同时,由于其结构的多样性和复杂性,以及循环系统中释放的小分子毒素含量较低等特殊性,给其药代动力学研究带来了诸多挑战。本文将从ADC药物的分子设计、药代动力学特征和目标分析物等方面讨论,以期帮助读者更好的理解ADC药物的药代动力学研究。     

The therapeutic equivalence of complex drugs

When the patent of a small molecule drug expires generics may be introduced. They are considered therapeutically equivalent once pharmaceutical equivalence (i.e. identical active substances) and bioequivalence (i.e. comparable pharmacokinetics) have been established in a cross-over volunteer study. However this generic paradigm cannot be applied to complex drugs as biologics and a number of other therapeutic modalities. For copies of biologics the European Medicine Agency and other regulatory agencies have introduced a new regulatory biosimilar pathway which mandates clinical trials to show therapeutic equivalence. However for other complex drugs such as the iron-carbohydrate drugs, low molecular weight heparins (LMWHs), liposomal drugs and the glatiramoids regulatory guidance is still mostly lacking. In this paper we will discuss (therapeutic) experience obtained so far with these different classes of 'complex drugs' and their specifics to provide scientific arguments and criteria for consideration for a regulatory framework for the market authorization for these type of drugs.