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Animal models of human disease: Challenges in enabling translation

机译：人类疾病的动物模型：实现翻译的挑战

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Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology, target identification, and in the in vivo evaluation of novel therapeutic agents and treatments. In the wake of numerous clinical trial failures of new chemical entities (NCEs) with promising preclinical profiles, animal models in all therapeutic areas have been increasingly criticized for their limited ability to predict NCE efficacy, safety and toxicity in humans. The present review discusses some of the challenges associated with the evaluation and predictive validation of animal models, as well as methodological flaws in both preclinical and clinical study designs that may contribute to the current translational failure rate. The testing of disease hypotheses and NCEs in multiple disease models necessitates evaluation of pharmacokinetic/pharmacodynamic (PK/PD) relationships and the earlier development of validated disease-associated biomarkers to assess target engagement and NCE efficacy. Additionally, the transparent integration of efficacy and safety data derived from animal models into the hierarchical data sets generated preclinically is essential in order to derive a level of predictive utility consistent with the degree of validation and inherent limitations of current animal models. The predictive value of an animal model is thus only as useful as the context in which it is interpreted. Finally, rather than dismissing animal models as not very useful in the drug discovery process, additional resources, like those successfully used in the preclinical PK assessment used for the selection of lead NCEs, must be focused on improving existing and developing new animal models.
机译：历史上，动物模型在疾病病理生理学的探索和表征，靶标的识别以及新型治疗剂和治疗方法的体内评估中发挥了关键作用。在新的化学实体（NCE）具有可观的临床前概况的众多临床试验失败之后，所有治疗领域的动物模型因预测人类NCE功效，安全性和毒性的能力有限而受到越来越多的批评。本综述讨论了与动物模型的评估和预测验证有关的一些挑战，以及临床前和临床研究设计中的方法缺陷，这些缺陷可能会导致当前的翻译失败率上升。在多种疾病模型中对疾病假设和NCE进行测试需要评估药代动力学/药效学（PK / PD）关系，以及较早开发的经过验证的与疾病相关的生物标记物以评估靶标参与和NCE疗效。另外，为了获得与当前动物模型的验证程度和固有局限性一致的预测效用水平，从动物模型获得的功效和安全性数据到临床前生成的分层数据集中的透明集成至关重要。因此，动物模型的预测值仅与解释它的上下文一样有用。最后，除了摒弃动物模型在药物开发过程中不是很有用之外，还必须将其他资源（如用于选择先导NCE的临床前PK评估中成功使用的资源）集中在改善现有和开发的新动物模型上。

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