Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, SE1 9NH, UK; Department of Pharmacology, Envigo CRS, Woolley Road, Alconbury, Huntingdon, Cambs, PE28 4HS, UK.
Department of Pharmacology, Envigo CRS, Woolley Road, Alconbury, Huntingdon, Cambs, PE28 4HS, UK.
Pulm Pharmacol Ther. 2018 Aug;51:73-78. doi: 10.1016/j.pupt.2018.07.002. Epub 2018 Jul 5.
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a poor prognosis and limited treatment options. Many compounds have shown efficacy in preclinical models of this condition, but only pirfenidone and nintedanib have been approved for clinical use. It is widely accepted that the current animal models of IPF need to be improved and in this review we have critically evaluated the current state of play of preclinical models of IPF and discuss the challenges facing this field. The popular model of a single intratracheal (I.T.) administration of bleomycin could be adapted to provide a more progressive fibrosis as is thought to occur in humans. Furthermore, currently the majority of new drugs are investigated in preclinical models of IPF are dosed using a prophylactic dosing regimen, whereas patients are almost always treated after the fibrosis is well established. Using a therapeutic dosing regimen in preclinical models would be a better way to establish potential efficacy of new drugs. The most popular endpoints examined in pre-clinical models of IPF are histological scoring and lung collagen content. However in IPF patients imaging and lung function tests are more commonly used as end points. We propose that examining more clinically relevant endpoints in pre-clinical models could also provide give a better indication of a compound's potential efficacy on endpoints measured in patients.
特发性肺纤维化 (IPF) 是一种致命的间质性肺疾病，预后不良，治疗选择有限。许多化合物在这种疾病的临床前模型中显示出疗效，但只有吡非尼酮和尼达尼布被批准用于临床使用。人们普遍认为，目前的 IPF 动物模型需要改进，在这篇综述中，我们批判性地评估了 IPF 临床前模型的现状，并讨论了该领域面临的挑战。目前，人们普遍认为，单次气管内（I.T.）给予博来霉素的流行模型可以适应提供更渐进的纤维化，正如人们认为在人类中发生的那样。此外，目前大多数新药在 IPF 的临床前模型中都是通过预防性给药方案进行研究的，而患者几乎总是在纤维化已经确立后才接受治疗。在临床前模型中使用治疗性给药方案将是确定新药潜在疗效的更好方法。在 IPF 的临床前模型中检查的最受欢迎的终点是组织学评分和肺胶原蛋白含量。然而，在 IPF 患者中，影像学和肺功能测试更常用于作为终点。我们提出，在临床前模型中检查更具临床相关性的终点也可以更好地表明化合物在患者测量的终点上的潜在疗效。
