In silico human-based methodologies for evaluation of drug cardiac safety and efficacy

药物毒性是药物开发失败的主要原因之一，更令人担忧的是，在上市批准后。由于心脏毒性而停药的比例从5.1%增加到33%，包括治疗心血管问题的化合物以及不打算影响心脏的药物。药物毒性表现为对心脏电生理学的不良影响，如心律失常和猝死，以及收缩性和结构的改变，包括例如心力衰竭和心肌梗死的发生率增加。尽管用于药物安全性临床前筛选的动物方法多种多样，但由于不良结果，20-50%的高级候选药物不得不被放弃，即使在药物开发过程的后期。通过在药物开发过程的早期阶段采用计算机技术，这些数字可以大大减少，并且动物实验的成本更低。其主要目的是加速采用基于人体的计算机模拟方法，以评估心脏药物在行业、监管和临床环境中的安全性和有效性。具体目标包括：1）审查、整理和实施用于特定疾病状况（例如心力衰竭、心肌缺血、遗传性疾病和心肌病）的人体电生理学和收缩性计算机模型的综合数据库。2)基于现有模型，开发和鉴定计算机模拟人体模型，用于预测特定疾病条件下人体心脏电生理学和收缩力的不良结局，并使用体内和非原位记录进行校准。3)评价研究，以比较计算机模拟基于人类的预测与临床结果、当前动物方法和体外方法（包括干细胞衍生的心肌细胞）。4)规划和开展研讨会和传播活动，以确定和克服在工业、临床和监管环境中采用计算机模拟方法的障碍。该提案将考虑以下事实作为一个重要焦点：心脏毒性不良事件更可能发生在因冠状动脉疾病、心肌梗死和/或心力衰竭而心脏机电功能受损的患者中。这些很少在动物中重现，但它们被系统地用于药物评价。我们将创建所需的基础设施，以促进获得从离子通道到整个器官的专业知识和计算机多尺度人类心脏模型，用于一系列疾病，包括心力衰竭，心肌缺血和基因突变。这项令人惊叹的技术具有明显的优势，即专注于人类，但也能够针对特定患者的病情进行个性化，对行业中的药物安全性和有效性评估以及依赖动物试验的临床应用产生潜在的3R影响。此外，为了提供计算机模拟建模技术，该项目将促进跨部门工作组，包括学者，临床医生和工业合作伙伴，以定义评估标准，提高可信度并完善心脏毒性的计算机模拟人体模型，并设计策略以克服其吸收障碍，以完善，取代和减少药物安全性和有效性评估的动物实验。该项目得到了至少10个国家的监管、工业、临床和学术部门的广泛成员的大力支持，他们将为提高3R在国际动物实验中的计算机模型的形象做出贡献。

Cardiotoxicity is one of the leading causes of failure during drug development and also, more worryingly, after marketing approval. Withdrawal due to cardiotoxicity has increased from 5.1 to 33%, including compounds to treat cardiovascular problems as well as drugs not intended to affect the heart. Cardiotoxicity manifest itself as adverse effects on cardiac electrophysiology such as arrhythmias and sudden death, and alterations on contractility and structure including, for example, increased incidence of heart failure and myocardial infarction. In spite of the variety of animal methods for preclinical screening for drug safety, 20-50% of all advanced candidates have to be abandoned due to adverse outcomes, even late in the drug development process. These figures could be drastically reduced, and at a smaller cost of animal experimentation, by the adoption of in silico technologies in the earlier phases of the drug development process. The main aim is to accelerate the uptake of human-based in silico methodologies for evaluation of cardiac drug safety and efficacy in industry, regulatory and clinical settings. The specific objectives include: 1) Review, collation and implementation of a comprehensive database of human electrophysiology and contractility in silico models for specific disease conditions such as heart failure, myocardial ischemia, genetic disorders and cardiomyopathies. 2) Development and qualification of in silico human models for the prediction of adverse outcomes in human cardiac electrophysiology and contractility for specific disease conditions, based on existing models, and calibration with in vivo and ex situ recordings. 3) Evaluation studies to compare in silico human-based predictions to clinical outcomes, current animal methods, and in vitro methods including stem cell derived cardiomyocytes. 4) Planning and development of workshops and dissemination activities to identify and overcome barriers for the uptake of in silico methods in industrial, clinical and regulatory settings. The proposal will consider as an important focus the fact that cardiotoxic adverse events are more likely to occur in patients with compromised cardiac electromechanical function due to coronary artery disease, myocardial infarction and/or heart failure. These are rarely reproduced in animals, which are however systematically used for drug evaluation. We will create the infrastructure required to facilitate access to expertise and in silico multiscale human cardiac models from ion channels to the whole organ, for a range of conditions including heart failure, myocardial ischaemia, and genetic mutations. This amazing technology has the obvious advantage of a focus in human, but also the ability for personalisation to specific patients' conditions, with a potential 3Rs impact in drug safety and efficacy evaluation in industry, and also in clinical applications that also rely on animal testing. In addition, to delivering in silico modelling technology, the project will facilitate inter-sectorial working groups including academics, clinicians and industrial partners for the definition of evaluation criteria to increase the credibility and refine the in silico human models for cardiotoxicity, and to design strategies to overcome barriers for their uptake to refine, replace and reduce animal experimentation for drug safety and efficacy evaluation. The project is strongly supported by wide membership across regulatory, industrial, clinical and academic sectors located in at least ten countries, who will contribute to raising the profile of the in silico models for the 3Rs in animal experimentation, internationally.