Burt Tal, Vuong Le Thuy, Baker Elizabeth, Young Graeme C, McCartt A Daniel, Bergstrom Mats, Sugiyama Yuichi, Combes Robert
Burt Consultancy, LLC, Durham, NC, USA.
LTV Consulting, Davis, CA, USA.
Altern Lab Anim. 2018 Dec;46(6):335-346. doi: 10.1177/026119291804600603.
Phase 0 approaches, including microdosing, involve the use of sub-therapeutic exposures to the tested drugs, thus enabling safer, more-relevant, quicker and cheaper first-in-human (FIH) testing. These approaches also have considerable potential to limit the use of animals in human drug development. Recent years have witnessed progress in applications, methodology, operations, and drug development culture. Advances in applications saw an expansion in therapeutic areas, developmental scenarios and scientific objectives, in, for example, protein drug development and paediatric drug development. In the operational area, the increased sensitivity of Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), expansion of the utility of Positron Emission Tomography (PET) imaging, and the introduction of Cavity Ring-Down Spectroscopy (CRDS), have led to the increased accessibility and utility of Phase 0 approaches, while reducing costs and exposure to radioactivity. PET has extended the application of microdosing, from its use as a predominant tool to record pharmacokinetics, to a method for recording target expression and target engagement, as well as cellular and tissue responses. Advances in methodology include adaptive Phase 0/Phase 1 designs, cassette and cocktail microdosing, and Intra-Target Microdosing (ITM), as well as novel modelling opportunities and simulations. Importantly, these methodologies increase the predictive power of extrapolation from microdose to therapeutic level exposures. However, possibly the most challenging domain in which progress has been made, is the culture of drug development. One of the main potential values of Phase 0 approaches is the opportunity to terminate development early, thus not only applying the principle of 'kill-early-kill-cheap' to enhance the efficiency of drug development, but also obviating the need for the full package of animal testing required for therapeutic level Phase 1 studies. Finally, we list developmental scenarios that utilised Phase 0 approaches in novel drug development.
0期研究方法，包括微剂量给药，涉及使用低于治疗剂量的受试药物，从而实现更安全、更具相关性、更快且更廉价的首次人体试验（FIH）。这些方法在限制人类药物开发中动物使用方面也具有巨大潜力。近年来，在应用、方法、操作和药物开发文化方面均取得了进展。应用方面的进展表现为治疗领域、开发方案和科学目标的扩展，例如在蛋白质药物开发和儿科药物开发中。在操作领域，液相色谱串联质谱（LC-MS/MS）灵敏度的提高、正电子发射断层扫描（PET）成像效用的扩展以及腔衰荡光谱（CRDS）的引入，提高了0期研究方法的可及性和效用，同时降低了成本和放射性暴露。PET已将微剂量给药的应用范围从主要用于记录药代动力学，扩展到用于记录靶点表达、靶点结合以及细胞和组织反应的方法。方法学上的进展包括适应性0期/1期设计、组盒式和鸡尾酒式微剂量给药以及靶内微剂量给药（ITM）以及新的建模机会和模拟。重要的是，这些方法提高了从微剂量外推至治疗剂量暴露的预测能力。然而，取得进展可能最具挑战性的领域是药物开发文化。0期研究方法的主要潜在价值之一是有机会尽早终止开发，这不仅应用了“尽早终止、成本低廉”的原则来提高药物开发效率，还避免了治疗水平1期研究所需的全套动物试验。最后，我们列出了在新药开发中采用0期研究方法的开发方案。
