中国定量药理学研究的文献计量分析

目的:通过系统检索和分析中国定量药理学的论文发表情况,分析定量药理学在国内的发展状况,反映中国定量药理学领域的动态变迁及未来发展趋势。方法:检索Pubmed、Scopus、Web of Science、中国知网、维普和万方医学数据库采用文献计量学方法分析定量药理论文的发表情况、主要研究机构、研究领域和发展趋势。结果:截至2016年12月31日,201家中国研究机构发表中文论文472篇、英文论文212篇,其中SCI收载论文184篇。发表论文不少于10篇的机构有13家,发文量占总量的47.9%。论文内容以群体药动学建模为主,也包括药动学/药效学和生理药动学的研究。研究的药物主要集中于免疫抑制剂、抗菌药物和抗癫痫药物。此外,近年来以机制为基础的建模与仿真、疾病进展模型和以模型为基础的系统评价等方面也有愈来愈多的论文发表,与国际发展前沿相一致。结论:近年来,定量药理的研究内容逐渐拓展和深化,受到了越来越多学术机构、制药企业和政府药政监管部门的重视。数据共享和多中心协作将是未来的发展趋势。可以预见定量药理在新药研发和个体化用药中将发挥越来越大的作用。     

Impact of pharmacometrics on drug approval and labeling decisions: A survey of 42 new drug applications

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.     

Translational pharmacokinetics: challenges of an emerging approach to drug development in stroke

INTRODUCTION: There is increasing recognition of the importance of translational pharmacokinetics in stroke research, lack of which has been cited as one of the main contributing factors to failure of Phase III trials. AREAS COVERED: The article reviews the translational issues in administration, distribution and sampling in the pharmacokinetics of putative therapeutic drugs in stroke. In addition, the role of translational pharmacometrics in drug development is discussed. The review uses the anti-inflammatory agent, IL-1 receptor antagonist, as an example. The reader will gain an insight into the pitfalls that are commonplace in translating pharmacokinetics from the preclinical to the clinical scenario. The reader will also gain an understanding of the complexities of blood-central nervous system (CNS) barriers in relation to brain pharmacokinetics and the increasing use of translational pharmacometrics in stroke research. EXPERT OPINION: The translation of preclinical to clinical pharmacokinetics is a discipline that is traditionally overlooked and is likely to be a key factor responsible for failure of clinical trials. With a clear comprehensive insight into the benefits and limitations of translational pharmacokinetics in stroke, translational pharmacokinetics can be safely used to enhance the efficacy of clinical trials in stroke and their likelihood of success.     

Challenges in the transition to model-based development

Practitioners of the art and science of pharmacometrics are well aware of the considerable effort required to successfully complete modeling and simulation activities for drug development programs. This is particularly true because of the current, ad hoc implementation wherein modeling and simulation activities are piggybacked onto traditional development programs. This effort, coupled with the failure to explicitly design development programs around modeling and simulation, will continue to be an important obstacle to the successful transition to model-based drug development. Challenges with timely data availability, high data discard rates, delays in completing modeling and simulation activities, and resistance of development teams to the use of modeling and simulation in decision making are all symptoms of an immature process capability for performing modeling and simulation. A process that will fulfill the promise of model-based development will require the development and deployment of three critical elements. The first is the infrastructure--the data definitions and assembly processes that will allow efficient pooling of data across trials and development programs. The second is the process itself--developing guidelines for deciding when and where modeling and simulation should be applied and the criteria for assessing performance and impact. The third element concerns the organization and culture--the establishment of truly integrated, multidisciplinary, and multiorganizational development teams trained in the use of modeling and simulation in decision-making. Creating these capabilities, infrastructure, and incentivizations are critical to realizing the full value of modeling and simulation in drug development.     

My Career as a Pharmacometrician and Commentary on the Overlap Between Statistics and Pharmacometrics in Drug Development

As part of a series of articles celebrating the American Statistical Association's 175th anniversary in 2014, this article provides a historical perspective of key statistical contributions to pharmacometrics (the design, modeling, and analysis of experiments involving complex dynamic systems) as well as a commentary on the author's career as a pharmaceutical industry statistician and pharmacometrician. Individuals with training in various academic disciplines including pharmacokinetics, pharmacology, engineering, and statistics, to name a few, have pursued careers as pharmacometricians. While pharmacometrics has benefitted greatly from advances in statistical methodology, there continues to be tension and skepticism between biostatisticians and pharmacometricians as they apply their expertise to drug development problems. This article explores some of the root causes for this tension and provides some suggestions for improving collaborations between statisticians and pharmacometricians. The article concludes with a plea for more statisticians to consider careers as pharmacometrics practitioners.     

模型引导下免疫检查点抑制剂的研发

免疫检查点抑制剂作为一种新型的抗肿瘤治疗药物,因其对多种肿瘤卓越的疗效及良好的安全性得到广泛认可。基于定量药理学的发展应运而生的模型引导的药物研发(model-informed drug development,MIDD),能加速新药临床试验的进程,提高新药研究过程中决策的正确率,尤其是针对研发难度较大而需求甚广的免疫检查点抑制剂类新药。本文主要以帕博利珠单抗为例,阐述MIDD方法在免疫检查点抑制剂研发过程中的具体应用,包括研发早期有效给药方案的拟定,研发晚期评估临床疗效和验证给药方案的可行性,再至上市后给药方案的再评估及变更,为MIDD指导抗肿瘤新药的研发提供参考。     

定量药理学与儿童药物研发和合理用药

1引言 儿童合理用药是摆在世界各国临床药理学工作者和儿科医生面前一个亟待解决而又悬而难决的课题。长期以来，儿童作为弱势群体和人类的未来是社会大众的保护对象，伦理上不接受儿童作为药物试验的受试者。即使是常用于儿童的药物，也很少在儿童中试验过。     

The dose makes the medicine

Dose and time considerations in the development and use of a drug are important for assessing actions and side effects, as well as predictions of safety and toxicity. This article deals with epistemological aspects of dose selection by probing into the linguistic and cultural roots for the measure of medicine mediated by the medical doctor. Because toxicity is related to dose, historic and recent views suggest that less can be more. At low, medium and high dose levels, effects can differ not only quantitatively but also qualitatively. Dose-related target activation and recognition of enantiodromic thresholds between beneficial and toxic effects require elucidation of underlying events. Such studies, including hormesis and microdosing, call for extended ADME procedures with high-resolution methods in addition to the current low-resolution approaches. Improved information of drug logistics and target pharmacokinetics enables effective drug selection, dose determination and prediction. It also allows considerations of systems biology [i.e. integral (gestalt) pharmacology] exemplified by the drug homunculus, as in the case of vitamin D, that might lead to new paradigms and drug design.     

Optimizing dose regimens and fixed dose combination ratios in clinical trials

Successful treatment of many diseases depends on the level of drug concentration in blood and its maintenance over a period of time around a value considered as therapeutic. The dose regimen that minimizes the underexposure and overexposure around the target concentration maximizes efficacy and safety, resulting in increased chances of a successful patient recovery. We present a method of computer-assisted dose finding by explicit optimization of a target criterion. We develop a general theory for such dose regimens and propose criteria for their computation. This approach is likely to supersede “brute force” techniques exclusively based on simulation. In case of a combination of two drugs in a single dosing unit, it is crucial that the optimal combination ratio is identified during the developmental process and is taken forward to further trials or approval. The algorithm computes the optimal ratio along with the optimal dose regimen. If the interest is in restricting the concentration profile of the drug to a therapeutic range, we adapt the algorithm to determine the optimal dose regimen. In future, this work is intended to aid the development of fixed dose combinations, especially antimalarials and other anti-infectives. The methodology also has potential applications in randomized concentration-controlled trials where adherence to the target concentration is a fundamental requirement.     

The formulation of lipid-based nanotechnologies for the delivery of fixed dose anticancer drug combinations

The introduction of combination chemotherapeutic regimens for the treatment of childhood leukaemia in the 1960s provided the proof-of-principle that cytotoxic drugs were capable of curing cancer. However, in the four decades since this discovery, the majority of cancers still cannot be cured by chemotherapy. Clinical evidence supports the hypothesis of Goldie and Coldman that treating cancers with all the available effective agents simultaneously provides the greatest chance of eliciting a cure. Unfortunately, for traditional cytotoxic agents with narrow therapeutic indices, life-threatening toxicity precludes combination chemotherapy regimens employing multiple agents. This review discusses the concept of fixed dose combination chemotherapy with emphasis on capturing therapeutic efficacy described as synergistic as a basis for improving the effectiveness of combination chemotherapy. The use of lipid-based nanotechnologies, focusing on liposomes, as an enabling technology to facilitate the delivery of cytotoxic agents to the tumour site at concentrations and/or drug ratios judged to be synergistic will be discussed. It is envisaged that the development of this model system will be supported by cell-based screening technologies, pharmacokinetic and pharmacodynamic parameters and mathematical models describing therapeutic drug:drug interactions (the Median Effect Principle of Chou and Talalay). Experiments using preclinical models are presented to support the benefits of drug delivery systems as a foundation for fixed dose anticancer drug combinations. The ultimate goal of this research is to prepare a 'single vial' fixed dose combination product that encompasses both traditional cytotoxic agents and new molecularly targeted modalities with optimum therapeutic effects and acceptable toxicity.     

Innovations and perspectives of metered dose inhalers in pulmonary drug delivery.

The phase-out of chlorofluorocarbons (CFCs) has spurred the development of alternative pulmonary drug delivery systems to pressurized metered dose inhalers (MDIs), such as dry powder inhalers and pocket size nebulizers. Reformulation of CFC-MDIs with hydrofluoroalkanes (HFAs) 134a and 227 is also an opportunity to improve these widely accepted systems with respect to ease of handling, compliance, dosing, and more reliable and efficient lung deposition. MDIs have the advantage to protect the drug substance from external parameters such as temperature and humidity and to meter and de-agglomerate the drug independent from patients inspiratory flow rates. Novel formulation technologies combined with improved valves and actuators should help to overcome dose uniformity and priming problems and will increase the percentage of fine particles capable of reaching the deeper regions of the lungs. Spacer mouthpieces can reduce the cold freon effect and undesired oropharyngeal deposition caused by the rapid evaporation of the propellant and plume velocity of the aerosol cloud. More advanced delivery devices may allow the patient to inhale at predetermined flow rates (fast/slow) to target the deposition of fine drug particles (1-6 microm) to specific sites into the lungs. Breath-actuated devices make these systems more effective and patient friendly. The above features in combination with numerical counters showing the remaining number of shots, and built-in blocking mechanisms to avoid tail-off dependent dose uniformity problems of the last labeled shots, should help to improve both acceptance and compliance of pMDIs compared to other inhalation devices. However, only those inhalation systems, which are accepted and appreciated by patients and offering an ambulatory treatment at reasonable cost, will be successful in a more and more competitive market. These issues must be considered in the development of future devices and formulations.     

Pharmacometrics: a multidisciplinary field to facilitate critical thinking in drug development and translational research settings

Pharmacometrics has evolved beyond quantitative analysis methods used to facilitate decision making in drug development, although the application of the discipline in this arena continues to represent the primary emphasis of scientists calling themselves pharmacometricians. While related fields populate and interface with pharmacometrics, there is a natural synergy with clinical pharmacology due to common areas of research and the decision-making expectation with respect to evolving conventional and translational research paradigms. Innovative and adaptable training programs and resources are essential in this regard as both disciplines promise to be key elements of the clinical research workplace of the future. The demand for scientists with pharmacometrics skills has risen substantially. Likewise, the salary garnered by those with these skills appears to be surpassing their counterparts without such backgrounds. Given the paucity of existing training programs, available training materials, and academic champions, a virtual faculty and online curriculum would allow students to matriculate into one of several programs associated with their advisor but take instruction from faculty at multiple institutions, including instructors in both industrial and regulatory settings. Flexibility in both the curriculum and the governance of the degree would provide the greatest hope of addressing the short supply of trained pharmacometricians.     

The Use of Pharmacometrics to Optimize Biosimilar Development

Pharmacometric approaches can assist in biosimilar development by leveraging quantitative knowledge of the originator product characteristics such as dose–exposure and exposure–response information to support a targeted approach to clinical studies. The degree to which these approaches can be applied relies on the level of information known about the originator and information that supports application of the originator model to the biosimilar. A model-based approach testing the hypothesis that the biosimilar PK and/or PK/PD profile is similar to the originator in the target patient population is aligned with the central comparability exercise required for the biosimilar approval. This Commentary details the key opportunities in study design and study analysis where pharmacometrics approaches can aid biosimilar development.     

现代定量药理学的研究进展及展望

定量药理学是运用数学和统计方法,定量研究药理作用规律的一门分支学科,该学科在新药研发及临床药物治疗中正在发挥愈来愈重要的作用。近年国外学界提出了基于模型的新药研发等新理念,将定量药理学的重要性提升到了新的高度,定量药理学正迈入一个新的时代。国内该学科已有二十多年的发展历史,打下了良好的基础,但较国际先进水平还有一定差距,目前正面临着新的发展契机,机遇与挑战并存。本文首先辨析了学科定义,并简要回顾了国内外的学科发展简史;重点介绍了该学科的重要研究领域及热点技术,包括群体药动学/药效学、暴露-反应（药动学-药效学）关系、临床试验模拟、新型临床试验设计、生物标记物、疾病模型和试验模型、建模与模拟的方法学等;简介了基于模型的新药研发的新理念;最后,对该学科的国内发展前景进行了展望。     

创新性药物临床试验剂量和给药方案的探索和确定

在创新性药物临床试验中，从最初人体初始剂量的设定到最后确定临床给药剂量和方法是业界普遍关心的问题，也是目前制约我国创新性药物研发水平提升的重要瓶颈之一。本文结合有关文献和具体审评实践，探讨创新性药物临床试验剂量的探索和确定方法。     

Factorial dose-response studies using frequency and magnitude of dose

In the early stages of traditional drug development, the frequency of dosing (e.g., QD, BID, etc.) is typically determined by the pharmacokinetic properties of a compound. After an appropriate dose frequency is chosen, the magnitude of dose is then evaluated via parallel-group dose-response trials. For some drugs, however, blood levels at any given time may not be accurate predictors of clinical response, or the drug may not be absorbed systemically. In those instances, we propose the use of a factorial dose-response trial that simultaneously evaluates frequency of dosing and magnitude of dose. We consider this approach to selecting an appropriate dosing regimen to be more scientifically founded and more cost-effective, than independent evaluation of dose and frequency through separate clinical trials. Some design considerations and statistical analysis strategies for these factorial trials are presented in this paper.     

Common Best Practice in Modeling and Simulation Across Quantitative Disciplines: A Comparison of Independently Emerging Proposals

In the last decade, a number of initiatives to define good practices for projects involving modeling and simulation have been put forward. No proposal for best practice in modeling and simulation, however, has been generally and consciously adopted in the pharmaceutical world. This perspective aims to highlight two recent proposals with respect to the use of modeling and simulation in the drug development and regulatory approval process. Both groups define Model-Informed Drug Discovery and Development (MID3) inclusively so as to potentially include the whole community of users of modeling and simulation. Applications in both communities (pharmacometrics and statistics) have many similarities in tools and methods to be used for model building, assumption testing, qualification versus available data, and sensitivity analysis, albeit with a different focus. Both communities are emphatic that the same good practices could apply across the wide range of modeling and simulation applications. A wider adoption of these common good practices in modeling and simulation across and between communities and practitioners is expected to enhance decision-making across drug research and development and regulatory environments.     

Modelling approaches to dose estimation in children

Most of the drugs on the market are originally developed for adults and dosage selection is based on an optimal balance between clinical efficacy and safety. The aphorism 'children are not small adults' not only holds true for the selection of suitable drugs and dosages for use in children but also their susceptibility to adverse drug reactions. Since children may not be subject to dose escalation studies similar to those carried out in the adult population, some initial estimation of dose in paediatrics should be obtained via extrapolation approaches. However, following such an exercise, well-conducted PK-PD or PK studies will still be needed to determine the most appropriate doses for neonates, infants, children and adolescents.