Role of transport proteins in drug discovery and development: a pharmaceutical perspective

1.?This review will explore, from a pharmaceutical industry perspective, the evidence and consequences of transport protein involvement in pharmacokinetic variability and safety of drugs in humans. With the preclinical and clinical evidence available, the transport proteins that are considered to be the most important in respect of pharmacokinetic variability and safety in humans will be highlighted.

2.?A large number of transport proteins have been identified, at both the genetic and the cellular level, which have been suggested to play some role in the absorption, distribution or elimination of endogenous, xenobiotic or drug substrates.

3.?The weight of evidence suggests that only a small number of transport proteins need to be routinely considered in the drug-discovery setting driven by the magnitude of their impact on tissue distribution, pharmacokinetic variability and drug–drug interactions.

4.?For the majority of candidate drugs, an assessment of the role of transporter proteins in their disposition and safety need only be assessed if in vivo properties suggest that active transport is likely to be a significant factor, if transport proteins are implicated in a particular therapeutic target area or if the disposition and safety of a likely co-medication are known to be significantly modulated by transport proteins.     

儿童生长发育对药物作用的影响及意义

儿童用药不同于成人，随着年龄增长身体的发育会影响药物的吸收、分布、代谢及清除等许多方面。从而影响药物的药代动力学。儿童的用药量及用药间隔随年龄增长而有所变化，临床上儿童用药应当制订与年龄相适应的最佳方案，而不是简单的按体重或年龄给药。     

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。     

Autoradioluminography,a powerful and reliable tool for drug development: Accelera's experience

A deeper understanding of the pharmacokinetic and pharmacodynamic properties of a drug candidate is a pivotal component of drug discovery and development. Autoradiography is an excellent technique allowing exploiting the advantages of the use of radioisotopes in the drug disscovery field. The introduction of phosphor imaging technology has revolutionized the handling of drug distribution studies providing high‐resolution images. Specifically, quantitative whole‐body autoradioluminography is employed for preclinical study where the aim is to obtain information about the route of elimination and tissue distribution of a drug candidate. Autoradioluminography is also the technique of choice pursued to deal with all the issue that it is possible to encounter in all stage of drug development (ie, site‐specific drug localization and retention, drug‐drug interactions, penetration into specific target, specific tissue binding, crossing of brain blood barrier, and placental transfer). The purpose of this review is to give a picture of how autoradiography is employed in our laboratory as a key tool for advances in the assessment of the drug disposition and to validate new experimental models.     

The impact of molecular targets in cancer drug development: major hurdles and future strategies

The last decades were characterized by enormous technological advances resulting in a better understanding of disease pathologies and improvement of treatment strategies. The development of targeted drugs, whose beginning can be traced back to Paul Ehrlich’s theory of the ‘magic bullet’ approximately 100 years ago, is today widely appraised as a promising strategy to combat benign, as well as malignant, diseases. Over 40 years after US President Nixon declared the ‘war on cancer’, treatment outcome, especially of solid tumors in the advanced stages of disease, still lies far behind expectations. In this perspective article, the authors discuss the recent development of targeted cancer drugs and identify major hurdles. The authors further highlight future strategies that might improve and accelerate the drug-development process.     

The clinical pharmacologist in drug discovery and development

1 Clinical pharmacology is a key activity in drug discovery and drug development with much to contribute to drug innovation.
2 However, very few clinical pharmacologists choose the pharmaceutical industry as their ultimate career.
3 Medical alumni of the RPMS clinical pharmacology department illustrate this; only four industrial careers vs thirty professors of clinical pharmacology or medicine.     

系统生物学——药物研发的新动力

系统生物学是研究生物系统中所有组成成分以及特定条件下这些组分间相互关系的学科。它以干涉生物活动过程及人工模拟为主要手段，以生物信息为基础，是近年提出的新研究领域，其主要特点是对已有生命科学认识的系统整合。系统生物学的理论与方法以及相关的研究结果将为新药研发以及中医药研究提供新的视角与手段，成为药物研究的新动力。     

The role of adaptive trial designs in drug development

Introduction: Clinical development of new drugs is a long and costly process. There is a need to find solutions which can improve and shorten this process. By introducing flexibility in to the design of clinical trials, adaptive design contributes to this improvement and allows to reach drug development decisions in a quicker way.

Areas covered: We review the main methodological approaches to adaptive trial design, introducing key statistical concepts. For each phase of the clinical development, different uses and implementations of adaptive trial (AD) design are presented and examples of recent clinical trials are given. The guidance documents issued by the US and European regulatory authorities are also presented.

Expert commentary: Despite inevitable challenges, prospects of this rapidly evolving approach to drug development are important. Controlling the risk of type 1 error and the potential operational risks which may be associated with adaptive trial strategy is paramount in late phase studies. However, with new methodological work, these risks are now well controlled and adaptive trial design will certainly shape the future of drug development.     

Comparison of EMA and FDA guidelines for drug interactions: An overview

In 2013, the regulatory authorities of the European Union and the US issued, almost simultaneously, new editions of the industry guidelines for the requirements of drug testing during their development for drug–drug and drug–food interactions. That being said, there are significant differences in the requirements set by both guidelines, and the aim of this article is to point out those differences. In this review, the author carefully and comprehensively compared the publicly available guidelines via the official Food and Drug Administation’s (FDA) and European Medicine Agency’s (EMA) websites, highlighting the differences between the two sets. Unlike the guidelines provided by the FDA, the EMA guidelines lack set requirements for testing interactions with therapeutic proteins as well as with the usage of pharmacodynamics end-points. It also does not set standards for the use of the ‘no interaction’ declaration in the summary of product characteristics. On the other hand, the FDA currently lacks guidance for testing drug–food interactions, the use of the Relative Induction Score correlation method, and proving existence of reversible inhibition and mechanism-based inactivation. It is important to note that, while there are differences in the requirements for the FDA’s and the EMA’s drug interaction guidelines, they are not substantial and are mostly relating to the scope of requirements and precision of the standards set.     

Tuberculosis susceptibility – implications for drug development and therapy

Psoriasis is a chronic inflammatory condition affecting 1 – 3% of the world’s population. Despite the availability of several agents, therapeutic options remain limited. With a better understanding of the pathophysiology of psoriasis, several potential therapeutic targets have been identified. Peroxisome proliferator activated receptors have been shown to play a role in cutaneous homeostasis. This review focuses on the potential therapeutic role of peroxisome proliferator activated receptor-γ agonists in psoriasis and the possibility for the future prospects.     

我国发展药物大品种的关键因素分析与规制政策探讨

目的：探讨我国发展药物大品种的关键因素和规制政策。方法：选取政府、企业、学术机构各单位的专家学者进行访谈,然后采用扎根理论分析访谈资料。结果：界定出药物大品种的概念范围,明确了我国建立药物大品种的必要性,分析出药物大品种改造的产业政策,并提出我国药物大品种改造的政策规制模型。结论：政府建立政策、完善制度,引导企业发展;企业加强自身创新能力、开拓国际市场,推进大品种的改造。     

介导候选药代谢的肝细胞色素P450酶表型鉴定的定性和定量方法

新药研发需要对候选药物的代谢途径、每个代谢途径对总清除率的贡献以及参与代谢的酶进行详细研究。候选药物经过肝细胞色素P450(CYP)酶代谢的比例(f_m)可以用放射性同位素标记的方法在人体水平测定,而肝中某酶亚型的代谢占总的CYP参与代谢的比例(f_CYPi)可以用体外酶表型鉴定的方法来测定,这两个参数的乘积f_m×f_CYPi即为某个CYP酶亚型代谢参与某候选药物体内清除的百分比,对研究体内药物-药物相互作用具有重要意义。本文从定性和定量两方面综述体外酶表型鉴定的研究方法。     

Molecular imaging with copper-64 in the drug discovery and development arena

The contribution of positron emission tomography (PET) to the drug discovery and development (D3) pipeline has been inhibited by the short half-lifes of PET radioisotopes, ¹¹C and ¹⁸F, poor availability and the high cost of infrastructure. Copper-64 (⁶⁴Cu) has a 12.7 h half-life, simple yet flexible radiochemistry and imaging characteristics that make it ideal for a wider application across the D3 arena. Recent scientific breakthroughs in the production of ⁶⁴Cu show that it's, commercial production can be made more widely available. More importantly, for pharmaceutical research and development programmes wishing to incorporate the high sensitivity and spatial resolution of PET, but no desire to implement and maintain expensive radiochemistry infrastructure, ⁶⁴Cu is an exciting option.