Hepatic Clearance Chip for Pharmacokinetics

用于药代动力学的肝脏清除芯片

• 批准号: 10761027
• 负责人: Murat Cirit
• 金额: $ 100.96万
• 依托单位: JAVELIN BIOTECH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761027
• 关键词: 3-Dimensional; Acceleration; Adoption; African American; Albumins; Algorithms; Animal Model; Animals; Architecture; Asian; Biliary; Biological; Biological Markers; Canis familiaris; Caucasians; Cells; Clinical; Clinical Trials; Coculture Techniques; Collection; Complex; Computer software; Consumption; Data; Data Analyses; Development; Differential Equation; Diffusion; Drug Combinations; Drug Industry; Drug Interactions; Drug Kinetics; Ensure; Enzymes; Equipment; Ethnic Origin; Evaluation; Excretory function; Family suidae; Fee-for-Service Plans; Female; Financial Hardship; Hepatic; Hepatocyte; Hispanic; Human; In Vitro; Industry; Lead; Liver; Mass Spectrum Analysis; Measurement; Measures; Mediating; Metabolic; Metabolic Clearance Rate; Metabolism; Methods; Modeling; Outcome; Patients; Perfusion; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Physiological; Physiology; Population; Pre-Clinical Model; Productivity; Property; Qualifying; Rattus; Readiness; Reproducibility; Reproducibility of Results; Risk; Risk Reduction; Rodent; Safety; Sampling; Service delivery model; Small Business Innovation Research Grant; Suspensions; System; Technology; Testing; Time; Tissue Engineering; Tissue Microarray; Tissues; Training; Translating; Translations; Urea; candidate selection; clinical predictors; clinical translation; cloud based; commercialization; cost; cost effective; design; drug candidate; drug clearance; drug development; drug discovery; drug disposition; drug metabolism; improved; in silico; in vivo; insight; lead optimization; liver function; male; manufacturing scale-up; microphysiology system; nonhuman primate; novel strategies; predict clinical outcome; research and development; scale up; small molecule; tool; uptake; usability

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.

药物代谢和药代动力学测试（DMPK）对于理解清除机制至关重要， 清除率和电极导线优化之前小分子药物的任何潜在药物-药物相互作用 开始人体临床试验。DMPK测试目前使用动物模型进行，通常是大鼠。 然而，这些研究是有问题的，原因如下：1）基于动物的DMPK研究是昂贵的， 在铅优化过程中创建一个大的财务负担;前20制药公司花费>$1.2 每年用于PK测试的动物超过100万只; 2）耗时 并延迟重要数据的收集。例如，每种化合物的合成都需要按比例放大 从μg到mg的数量，然后才能开始大鼠研究。3)而高等动物物种，如狗，猪， 和非人类灵长类动物，有更大的人类相关性，他们比啮齿类动物的研究更昂贵， 需要合成甚至更大量的活性药物成分（API）;和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 这些方法在可靠性、长期分析能力、再现性、反射差等方面都受到限制， 体内肝脏转运、清除和代谢。因此，制药行业需要更好的 DMPK测试的方法比目前可用的体外方法更具预测性，更便宜，更快， 体内方法。这种系统的成功开发将提高安全性，并有助于减少约90%的 目前在临床试验中失败的候选药物。 为了解决这一未满足的需求，我们提出了一种集成的（体外和计算机模拟）肝脏清除平台， 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肝脏 清除参数在2周内准确，无需API放大。标枪是唯一一个 追求这种技术的药物代谢和处置，这需要独特的设计特点， DMPK研究，并且无法使用为毒理学设计的微生理学系统来满足， 药理学应用本直接进入第二阶段SBIR提案的目的是改进我们的技术 通过优化芯片设计以提高可用性，评估药物清除机制， 评估我们技术的临床转化。这将通过以下目标实现：1）系统 设计优化; 2）Javelin上已知药物清除机制的评估和表征 肝清除芯片;和3）评估体外到体内的转化以预测临床结果。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的需要， 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临床结果15%，并且以10倍便宜的方式， 比老鼠研究快一倍。