Hepatic Clearance Chip for Pharmacokinetics

药物代谢和药代动力学测试(DMPK)对于了解药物清除机制至关重要。 在前导优化之前，小分子药物的清除率和任何潜在的药物-药物相互作用 启动人体临床试验。DMPK测试目前是使用动物模型进行的，通常是大鼠。 然而，这些研究存在问题的原因有几个：1)基于动物的DMPK研究昂贵且 在销售线索优化期间造成巨大的财务负担；排名前20位的制药公司花费1.2美元 每年进行PK测试，工业界每年使用的动物超过100万只；2)它们很耗时 并推迟重要数据的收集。例如，每种化合物的合成都需要放大。 从微克到镁的量，然后才能开始老鼠研究。3)而高等动物物种，如狗、猪、 和非人类灵长类动物，具有更大的人类相关性，它们比啮齿动物研究和 需要合成更多的有效药物成分(原料药)；以及4)动物的能力 预测人类结果的模型是有争议的。尽管最近已经尝试在体外鉴定 方法，这些都在可靠性、长期分析能力、重复性、反映差等方面受到限制 体内肝脏转运、清除和代谢的研究。因此，制药业需要更好的 DMPK检测方法比目前的体外和快速检测更具预测性、更便宜、更快 活体实验方法。这种系统的成功开发将提高安全性，并有助于减少~90%的 目前在临床试验中失败的候选药物。 为了解决这一未得到满足的需求，我们提出了一个集成的(体外和硅胶中)肝脏清除平台，该平台 融合了人类肝脏组织芯片和翻译软件。这项技术可以预测人类的肝脏 2周内清除参数准确，无需API扩容。标枪是唯一一个 追求这项用于药物代谢和处置的技术，这需要独特的设计特征 DMPK研究，不能使用毒理学和微生理系统设计的微生理系统 药理学应用。这项直接到第二阶段SBIR计划的目的是改进我们的技术 通过优化芯片设计以增强可用性、评估药物清除机制，以及 评估我们技术的临床翻译。这将通过以下目标来实现：1)系统 设计优化；2)标枪上已知药物清除机制的评估和表征 肝脏清除芯片；以及3)评估体外到体内的翻译以预测临床结果。成功 我们的组织芯片灌注系统的应用将减少对其他临床前模型评估药物的需求 PK结果，从而降低与药物开发相关的风险和成本。事实上，我们早期的证据 表明我们可以更准确地预测15%的临床结果，而且成本低10倍， 比老鼠研究快几倍。

Drug metabolism and pharmacokinetic testing (DMPK) is crucial for understanding the clearance mechanisms, clearance rate, and any potential drug-drug interactions of small molecule drugs during lead optimization prior to initiating in-human clinical trials. DMPK testing is currently performed using animal models, usually rats. However, these studies are problematic for several reasons: 1) Animal-based DMPK studies are expensive and create a large financial burden during lead optimization; the top 20 pharmaceutical companies spend >$1.2 billion each year on PK testing, with over 1 million animals used by industry per year; 2) They are time-consuming and delay the collection of important data. For example, the synthesis of each compound needs to be scaled up from µg to mg quantities before rat studies can be initiated. 3) While higher animal species, such as dogs, pigs, and non-human primates, have greater human relevance, they are more expensive than rodent studies and require synthesis of even greater quantities of active pharmaceutical ingredient (API); and 4) The ability of animal models to predict human outcomes is controversial. Although recent attempts have been made to identify in vitro approaches, these are all limited in terms of reliability, long-term analysis ability, reproducibility, poor reflection of in vivo hepatic transport, clearance, and metabolism. Thus, the pharmaceutical industry needs better approaches for DMPK testing that are more predictive, cheaper, and faster than currently available in vitro and in vivo methods. Successful development of such a system will improve safety and help reduce the ~90% of drug candidates that currently fail in clinical trials. In solution to this unmet need, we propose an integrated (in vitro and in silico) hepatic clearance platform that merges a human liver tissue chip and translational software. This technology can predict human hepatic clearance parameters accurately in 2 weeks without the need of API scale-up. Javelin is the only organization pursuing this technology for drug metabolism & disposition, which requires design features that are unique to DMPK studies and that cannot be met using microphysiological systems designed for toxicology and pharmacology applications. The purpose of this Direct to Phase II SBIR proposal is improve our technology ready for launch by optimizing the chip design to enhance usability, evaluate drug clearance mechanisms, and assess the clinical translation of our technology. This will be achieved through the following Aims: 1) System design optimization; 2) Evaluation and characterization of known drug clearance mechanisms on the Javelin hepatic clearance chip; and 3) Assessment of in vitro to in vivo translation to predict clinical outcomes. Successful application of our tissue chip perfusion system will reduce the need for other preclinical models to estimate drug PK outcomes, thereby reducing the risk and cost associated with drug development. Indeed, our early evidence indicates that we can predict clinical outcomes 15% more accurately and in a manner 10-times cheaper and 10- times faster than rat studies.