Microfluidic Liver Array for Drug Metabolite Profiling

用于药物代谢物分析的微流控肝脏阵列

基本信息

批准号：
8036092
负责人：
Paul Ju-Sung Hung
金额：
$ 44.48万
依托单位：
CELLASIC CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8036092
关键词：
7-ethoxycoumarin Adverse effects Animal Testing Animals Area Under Curve Biological Biological Products Bioreactors Cell Count Cell Survival Cells Clinic Clinical Collaborations Culture Media Dapsone Data Development Devices Dextromethorphan Diclofenac Drug Compounding Drug Interactions Europe Evaluation Grant Height Hepatocyte Human In Vitro Industry Letters Life Liver Longevity Marketing Measures Metabolic Methods Microfabrication Microfluidics Midazolam Modeling Molds Monitor Movement Perfusion Pharmaceutical Preparations Phase Phenacetin Positioning Attribute Problem Solving Process Production Publishing Reagent Reliance Resources Running Safety Savings Screening procedure Services Silicon Simulate Small Business Innovation Research Grant Staging System Technology Testing Thick Time Toxic effect Validation Variant Work base clinically relevant commercialization cost design drug development drug discovery drug metabolism enzyme activity improved in vivo in vivo Model meetings novel prototype public health relevance safety testing tool

项目摘要

DESCRIPTION (provided by applicant): CellASIC has developed a novel microfluidic technology to integrate 32 bioreactors on a standard 96-well plate for multiplexed perfusion culture of primary human hepatocytes with demonstrated long-term viability and liver-enzymatic function. This Phase 1 SBIR will utilize this technology to develop and validate an in vitro screening platform for liver-specific drug metabolite profiling. Model compounds will be used to assess metabolic activities, with analysis via LC-MS/MS with our collaborators at BD Biosciences. Once the validation is complete, the company positioned to quickly make the product available to the marketplace. Drug metabolite profiling using primary human hepatocytes has gained more importance in the past decade as it has become recognized that drug metabolism is closely related to drug safety. The FDA has recently issued guidance on drug-drug interaction tests as well as drug safety testing of drug metabolites. Additionally, there is a strong movement in the US as well as in Europe to reduce animal trials and develop improved in vitro technologies. However, the state-of-the-art in vitro drug metabolism models only predict around 50% of the in vivo metabolites, partly because primary hepatocytes rapidly degrade in culture and lose their liver-enzymatic functions. PUBLIC HEALTH RELEVANCE: CellASIC is developing a microfluidic liver array (MLA) system that will allow biopharmaceutical companies to more accurately predict the adverse effects of new drug compounds on human liver prior to clinical and animal studies. Key benefits include safer drugs in the clinic, reduced cost per data point, more clinically relevant data at an earlier stage, reduced reliance on animal testing, and improved understanding of toxicity mechanisms.

描述（由申请人提供）：Cellasic开发了一种新型的微流体技术，可以在标准的96孔板上整合32个生物反应器，以使原代人肝细胞的多路复用灌注培养具有长期的生存能力和肝功能。该第1阶段SBIR将利用这项技术来开发和验证肝特异性药物代谢物分析的体外筛查平台。模型化合物将用于评估代谢活动，并通过LC-MS/MS与BD Biosciences的合作者进行分析。验证完成后，该公司就可以快速将产品提供到市场上。在过去的十年中，使用原代人肝细胞的药物代谢产物分析变得越来越重要，因为它已经认识到药物代谢与药物安全密切相关。 FDA最近发布了有关药物相互作用测试的指南以及药物代谢物的药物安全测试。此外，在美国和欧洲都有强大的运动，以减少动物试验并发展得改进的体外技术。然而，最新的体外药物代谢模型仅预测了约50％的体内代谢产物，部分原因是原发性肝细胞在培养中迅速降解并失去其肝酶功能。公共卫生相关性：Cellasic正在开发微流体肝阵列（MLA）系统，该系统将使生物制药公司在临床和动物研究之前更准确地预测新药化合物对人肝脏的不利影响。关键好处包括在诊所中使用更安全的药物，每个数据点的成本降低，在较早阶段临床相关的数据，降低了对动物测试的依赖以及对毒性机制的了解。