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：
7804425
负责人：
Paul Ju-Sung Hung
金额：
$ 45.18万
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/7804425
关键词：
7-ethoxycoumarin Adverse effects Animal Testing Animals Area Under Curve Arts 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 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 discovery drug metabolism enzyme activity improved in vivo in vivo Model meetings novel prototype public health relevance research clinical testing 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 开发了一种新型微流体技术，可在标准 96 孔板上集成 32 个生物反应器，用于原代人肝细胞的多重灌注培养，并已证明具有长期活力和肝酶功能。第一阶段 SBIR 将利用该技术开发和验证用于肝脏特异性药物代谢物分析的体外筛选平台。模型化合物将用于评估代谢活动，并与 BD Biosciences 的合作者通过 LC-MS/MS 进行分析。验证完成后，该公司将迅速将产品推向市场。在过去十年中，使用原代人肝细胞进行药物代谢谱分析变得越来越重要，因为人们认识到药物代谢与药物安全性密切相关。 FDA 最近发布了药物相互作用测试以及药物代谢物的药物安全性测试指南。此外，美国和欧洲正在大力减少动物试验并开发改进的体外技术。然而，最先进的体外药物代谢模型只能预测大约 50% 的体内代谢物，部分原因是原代肝细胞在培养物中快速降解并失去其肝酶功能。公共健康相关性：CellASIC 正在开发一种微流控肝脏阵列 (MLA) 系统，该系统将使生物制药公司能够在临床和动物研究之前更准确地预测新药物化合物对人类肝脏的不利影响。主要好处包括临床药物更安全、每个数据点的成本降低、早期阶段有更多临床相关数据、减少对动物试验的依赖以及提高对毒性机制的了解。