New body-on-chip prototype for in vitro pharmacokinetic analysis and next-generation risk assessment of drugs

人类使用的新药的发现和开发仍然是一个缓慢、昂贵和低效的过程。药物发现计划失败的一个关键点是对候选药物进行临床前评估，但成功率仅为30%左右。因此，需要新的方法来提高临床前药物开发阶段的成功率。该项目旨在开发一种新的、环境可持续的原型设备，以实现药物体外药代动力学(PK)的高通量表征，并结合计算机动力学模型更好地预测药物在体内的表现。研究药物PK的金标准方法包括使用正电子发射断层扫描(PET)和微剂量技术。然而，这些技术可能会很昂贵，而且往往需要大量的动物。重要的是，尽管使用动物可以有用地评估药物分布、新陈代谢和治疗效果，但物种与人类的差异往往会降低新药的翻译成功率。因此，有必要设计更有效的药物发现管道，并在过程的早期阶段增加对先导化合物选择的信心。最近，我们的团队开发了一种新的“芯片上的身体”原型设备，它具有许多重要的特性，使其在“芯片上的身体”领域中独树一帜，即：通过毛细血管系统和能够模拟人体循环系统的器官舱进行灌流；易于使用和多功能的器官舱能够容纳大量细胞，这是通过高通量和主流色谱方法准确量化细胞中药物浓度所必需的；环境上可持续的可重复使用的设计，只需要在实验之间采用简单的清洁方案；降低了制造成本和维护成本，因为“芯片本体”可以重复使用，并且维持通过该装置的流量所需的相关蠕动泵是现成的。我们新的“芯片上身体”设备有可能在体外进行预测性PK研究，以及个别组织药物暴露分析和药物靶标结合动力学量化，这是目前现有的“芯片上身体”设备无法完成的。

Discovery and development of new drugs for human use remains a slow, expensive and inefficient process. A critical point of failure in drug discovery programmes is the preclinical evaluation of drug candidates with only about 30% success rate. Consequently, new methodologies to increase success rate at the preclinical drug development stage are needed. This project aims to develop a new, environmentally sustainable, prototype device to allow for high-throughput in vitro characterisation of drugs pharmacokinetics (PK) coupled with in silico kinetic models to better predict drug performance in vivo. The gold-standard approach to investigate drugs PK involves using Positron Emission Tomography (PET) and microdosing techniques. However, these techniques can be expensive and often require a large number of animals. Importantly, although the use of animals can be useful to assess drug distribution, metabolism and therapeutic effects, species differences versus humans often decrease the translational success rate of a new drug. Therefore, there is a need to design more efficient drug discovery pipelines and to increase confidence on selection of the lead compounds at early stages of the process. To this regard, the recent development of the so called "body-on-chip" in vitro technology holds tremendous promise as a platform to predict drug responses in vivo.Recently, our team has developed a new "body-on-chip" prototype device, which has a number of important properties that position it uniquely in the "body-on-chip" arena, namely: Perfusion through the capillary system and organ compartments capable of mimicking the human circulatory system; Easy to use and versatile organ compartment inserts capable of housing a large number of cells, required for accurate quantification of concentration of drugs in cells by high throughput and mainstream chromatographic methods; Environmentally sustainable re-usable design, requiring only a simple clean protocol between experiments; Reduced cost of manufacturing as well as reduced maintenance costs, as the "body-on-chip" can be re-used and the associated peristaltic pump required to maintain flow through the device is commercially available off the shelf. Our new "body-on-chip" device has the potential to enable predictive PK studies in vitro as well as individual tissue drug exposure analysis and drug-target binding kinetics quantification, which currently cannot be accomplished with available "body-on-chip" devices.