The clinical pharmacologist in drug regulation: a European perspective

1 The clinical pharmacologist in drug regulation has many roles to play. These include responsibilities for the premarketing assessment of a new product's efficacy and safety, for scrutiny of the summary of Product Characteristics, and for monitoring its performance after marketing. Furthermore, the clinical pharmacologist has a subsidiary responsibility in examining the results of preclinical pharmacological and toxicological studies.
2 Clinical pharmacologists in regulatory authorities have one further, and crucial, responsibility—humility. From their training and experience they will (or should) know of their own scientific limitations and of the necessity for seeking help and advice from other disciplines.     

Drug discovery and development: lessons from an undeveloped drug

In this article, drug discovery and preclinical development paradigms, as employed in today’s pharmaceutical companies, are discussed. The antimalarial drug, artemisinin, is given as an example of a compound that is unlikely to be developed by a modern pharmaceutical company, yet is a safe and effective drug for the treatment of a deadly disease. It is argued that the use of prespecified charts, listing undesired properties to deselect molecules may lead to missed opportunities in bringing best-in-class medications to patients. Implementation of systems pharmacology, disease progression and pharmacokinetic/pharmacodynamic models are proposed. These models offer a superior approach in selecting the best drug candidates with the highest chance of success of entry into the market.     

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.     

Reducing QT liability and proarrhythmic risk in drug discovery and development

Drug-induced torsades de pointes (TdP), a rare, life-threatening, polymorphic, ventricular tachycardia associated with prolongation of the QT interval, has been the main safety reason for the withdrawal of medicines from clinical use over the last decade. Most often, drugs that prolong the action potential and delay ventricular repolarization do so through blockade of outward (repolarizing) currents, predominantly the rapid delayed rectifying potassium current, I_Kr. While QT interval prolongation is not a safety concern per se, in a small percentage of people, it has been associated with TdP, which either spontaneously terminates or degenerates into ventricular fibrillation. Furthermore, recent data suggest that shortening of the QT interval may also be a new safety issue waiting to surface. This review article summarizes the presentations given at a symposium entitled ‘Reducing QT liability and proarrhythmic risk in drug discovery and development’, which was part of the Federation of the European Pharmacological Societies congress, Manchester, UK, 13–17 July 2008. The objective of this symposium was to assess the effects of implementing the latest regulatory guidance documents (International Conference on Harmonization S7A/B and E14), as well as new scientific and technical trends on the ability of the pharmaceutical industry to reduce and manage the QT liability and associated potential proarrhythmic risk, and contribute to the discovery and development of safer medicines. This review outlines the key messages from communications presented at this symposium and attempts to highlight some of the key challenges that remain to be addressed.This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010     

The emerging role of plasma lipidomics in cardiovascular drug discovery

Introduction: With the rising global incidence of cardiovascular disease, the challenge for the pharmaceutical industry is to identify novel biomarkers that will allow not only for the development of the next generation of cardiometabolic therapeutics, but also to serve as a sensitive mechanism to monitor and predict drug efficacy and potential toxicity. The advent of an ‘omics’ (systems biological) approach has vast implications for future disease treatment and prevention. Lipidomics is the latest addition to the ‘omics’ family and is rapidly gaining attention due to the technological improvements in mass spectrometry, allowing for the characterization of large number of lipids (and their respective subclasses) in a short amount of time with relatively minimal preparation.

Areas covered: The authors discuss the various techniques involved in plasma lipidomics as well as outline the role that lipidomics will play in phenotyping disease processes and corresponding therapeutic strategies. The article was formed through comprehensive Medline search of relevant publications in this area.

Expert opinion: Despite the wealth of data that will emerge regarding the various lipid–molecular interactions and the functions of lipids within cells, a major challenge will be the parallel emergence of novel bioinformatics platforms in order to integrate this enormous data set with information generated from the emerging fields of genomics and proteomic analysis. Despite these challenges, lipidomics is likely to result in the reclassification of diseases from a molecular perspective and play a key role the eventuation of personalized medicine.     

Principles and applications of Raman spectroscopy in pharmaceutical drug discovery and development

Introduction: In recent years, Raman spectroscopy has become increasingly important as an analytical technique in various scientific areas of research and development. This is partly due to the technological advancements in Raman instrumentation and partly due to detailed fingerprinting that can be derived from Raman spectra. Its versatility of applications, rapidness of collection and easy analysis have made Raman spectroscopy an attractive analytical tool.

Areas covered: The following review describes Raman spectroscopy and its application within the pharmaceutical industry. The authors explain the theory of Raman scattering and its variations in Raman spectroscopy. The authors also highlight how Raman spectra are interpreted, providing examples.

Expert opinion: Raman spectroscopy has a number of potential applications within drug discovery and development. It can be used to estimate the molecular activity of drugs and to establish a drug’s physicochemical properties such as its partition coefficient. It can also be used in compatibility studies during the drug formulation process. Raman spectroscopy’s immense potential should be further investigated in future.     

Promise and challenges in drug discovery and development of hybrid anticancer drugs

Background: Because cancer is a complex disease, it is unlikely that a single mono functional ‘targeted’ drug will be effective for treating this most advanced disease. Combined drugs that impact multiple targets simultaneously are better at controlling complex disease systems, are less prone to drug resistance and are the standard of care in cancer treatment. In order to improve the efficiency of using a two-drug cocktail, one approach involves the use of the so-called hybrid drugs, which comprises the incorporation of two drugs in a single molecule with the intention of exerting dual drug action.

Objective: In the present article, we discuss the design, synthesis and various applications of anticancer hybrid agents and the developments in this field during the last few decades. Additionally, we describe different types of linkers and their role in contributing towards biological effects and the in vivo mechanism of drug release. We also depict some challenges from scientific and regulatory perspectives in the hybrid drug development process.

Conclusion: In the era of increasing drug resistance in cancer patients, the discovery of hybrid drugs could provide an effective strategy to create chemical entities likely to be more efficacious and less prone to resistance. However, some technical and regulatory challenges will have to be surmounted before hybrid drugs succeed in the clinical settings and justify the considerable promise of this novel concept.     

Challenges for drug discovery and development in China

Introduction: The drug development industry is restructuring worldwide in terms of the research and development process. As with pharmaceuticals in the west, China faces major challenges for drug discovery and development.

Areas covered: In this review, the authors discuss anti-cancer, anti-allergy, anti-infectious, and proprietary Chinese Medicines (pCM) for various chronic diseases (such as the allergic diseases: eczema, asthma and allergic rhinitis), which remain the contemporary therapeutic strategies that are being explored and developed. Drug transporters, disease specific biomarkers, pharmacophores, bioactive natural products and pharmacogenetics are some aspects of research technologies. Proprietary Chinese medicine remains one of the most popular strategies. There is however the issue of good research documentation of efficacy versus adverse effects. China has a complex healthcare system involving a large patient pool.

Expert opinion: Various factors can impact drug development in China including the concurrent use of both western and Chinese medicines, pharmacogenetic variances, lack of multidisciplinary team impact on disease management and drug safety. China may adopt the current development of big data analysis in other countries such as UK and US to build and centralize a nationwide database for better monitoring and clinical evaluation to provide more efficient care at a lower cost.     

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。     

Opportunities to minimise risk in drug discovery and development

ABSTRACT

Introduction: Artificial neural networks (ANNs) are highly adaptive nonlinear optimization algorithms that have been applied in many diverse scientific endeavors, ranging from economics, engineering, physics, and chemistry to medical science. Notably, in the past two decades, ANNs have been used widely in the process of drug discovery.

Areas covered: In this review, the authors discuss advantages and disadvantages of ANNs in drug discovery as incorporated into the quantitative structure-activity relationships (QSAR) framework. Furthermore, the authors examine the recent studies, which span over a broad area with various diseases in drug discovery. In addition, the authors attempt to answer the question about the expectations of the ANNs in drug discovery and discuss the trends in this field.

Expert opinion: The old pitfalls of overtraining and interpretability are still present with ANNs. However, despite these pitfalls, the authors believe that ANNs have likely met many of the expectations of researchers and are still considered as excellent tools for nonlinear data modeling in QSAR. It is likely that ANNs will continue to be used in drug development in the future.     

Explainability and white box in drug discovery

Recently, artificial intelligence (AI) techniques have been increasingly used to overcome the challenges in drug discovery. Although traditional AI techniques generally have high accuracy rates, there may be difficulties in explaining the decision process and patterns. This can create difficulties in understanding and making sense of the outputs of algorithms used in drug discovery. Therefore, using explainable AI (XAI) techniques, the causes and consequences of the decision process are better understood. This can help further improve the drug discovery process and make the right decisions. To address this issue, Explainable Artificial Intelligence (XAI) emerged as a process and method that securely captures the results and outputs of machine learning (ML) and deep learning (DL) algorithms. Using techniques such as SHAP (SHApley Additive ExPlanations) and LIME (Locally Interpretable Model-Independent Explanations) has made the drug targeting phase clearer and more understandable. XAI methods are expected to reduce time and cost in future computational drug discovery studies. This review provides a comprehensive overview of XAI-based drug discovery and development prediction. XAI mechanisms to increase confidence in AI and modeling methods. The limitations and future directions of XAI in drug discovery are also discussed.     

The application of absolute quantitative 1H NMR spectroscopy in drug discovery and development

ABSTRACT

Introduction: The identification of a drug candidate and its structural determination is the most important step in the process of the drug discovery and for this, nuclear magnetic resonance (NMR) is one of the most selective analytical techniques.

Area covered: The present review illustrates the various perspectives of absolute quantitative ¹H NMR spectroscopy in drug discovery and development. It deals with the fundamentals of quantitative NMR (qNMR), the physiochemical properties affecting qNMR, and the latest referencing techniques used for quantification. The precise application of qNMR during various stages of drug discovery and development, namely natural product research, drug quantitation in dosage forms, drug metabolism studies, impurity profiling and solubility measurements is elaborated. To achieve this, the authors explore the literature of NMR in drug discovery and development between 1963 and 2015. It also takes into account several other reviews on the subject.

Expert opinion: qNMR experiments are used for drug discovery and development processes as it is a non-destructive, versatile and robust technique with high intra and interpersonal variability. However, there are several limitations also. qNMR of complex biological samples is incorporated with peak overlap and a low limit of quantification and this can be overcome by using hyphenated chromatographic techniques in addition to NMR.     

The future of quantum dots in drug discovery

The rapid development of drug discovery today is inseparable from the interaction of advanced particle technologies and new drug synthesis protocols. Quantum dots (QDs) are regarded as a unique class of fluorescent labels, with unique optical properties such as high brightness and long-term colloidal and optical stability; these are suitable for optical imaging, drug delivery and optical tracking, fluorescence immunoassay and other medicinal applications. More importantly, QD possesses a rich surface chemistry property that is useful for incorporating various drug molecules, targeting ligands, and additional contrast agents (e.g., MRI, PET, etc.) onto the nanoparticle surface for achieving targeted and traceable drug delivery therapy at both cellular and systemic levels. In recent times, the advancement of QD technology has promoted the use of functionalized nanocrystals for in vivo applications. Such research is paving the way for drug discovery using various bioconjugated QD formulations. In this editorial, the authors highlight the current research progress and future applications of QDs in drug discovery.     

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.     

网络药理学:药物发现的新思想

新药研发是医药产业发展的核心驱动力,也是社会发展的重要需求,但近年来,随着对药物研发要求的不断提高,新药研发正面临着巨大困难,单靶点高选择性的新药研发思想遇到了挑战,已经显示出发展的局限性。网络药理学是近年来在单靶点药物研究的基础上提出的新药发现新策略。本文围绕网络药理学的形成基础和目前研究现状,探讨网络药理学发展的方向和应用前景,同时分析网络药理学的局限性和存在的问题,并通过与传统中医药学理论和中药复方有效成分组学的思想相比较,探讨网络药理学在新药研发中的应用。