Bench-top human metabolism system for improved IVIVE in drug development

用于改进药物开发中 IVIVE 的台式人体代谢系统

• 批准号: 8832276
• 负责人: Randall Edwin McClelland
• 金额: $ 16.94万
• 依托单位: SCIKON INNOVATION, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2016-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832276
• 关键词: Accounting; Address; Adult; Animal Model; Animals; Biological; Biological Assay; Biological Availability; Biological Models; Biology; Bypass; Cadaver; Canis familiaris; Capital; Cell Culture Techniques; Cell model; Cells; Chemicals; Clinical Trials; Coculture Techniques; Communities; Coupling; Cryopreservation; Development; Devices; Drug Kinetics; Enterohepatic Circulation; Epithelial Cells; Epithelium; Failure; Goals; Health; Hepatocyte; Histocompatibility Testing; Human; Human Biology; Human body; In Vitro; Intestines; Investigational Drugs; Investments; Lead; Link; Liquid substance; Marketing; Measurement; Metabolic; Metabolism; Methods; Microfluidics; Miniaturization; Modeling; Organ; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiology; Population; Predictive Value; Process; Property; Research; Rodent; Safety; Series; Site; Small Intestines; Solutions; Staging; Symptoms; System; Technology; Testing; Tissues; Toxic effect; Training; Tumor-Derived; Work; base; biological systems; body system; culture plates; design; drug development; drug discovery; drug efficacy; efficacy testing; fluid flow; human tissue; improved; in vivo; innovation; intestinal epithelium; jejunum; liver metabolism; metabolic abnormality assessment; novel therapeutics; pre-clinical; research and development; research study; safety testing; species difference; tool; toxicant; uptake; user-friendly

DESCRIPTION (provided by applicant): Only 13% of investigational drugs that enter clinical trials make it to approval. Seventy-five percent of these failures are due to either unexpected toxicity or lack of efficacy discovered in phase I and II clinical trials. This high failure rate o drugs in late stage development is a symptom of the inadequacy of pre- clinical animal models to accurately predict human biology. Technologies based on human organ systems in vitro has the potential to overcome these limitations by enabling human relevant physiology to be studied earlier in the drug discovery process. In other words, development of more physiologically relevant in vitro systems grounded in human biology rather than animal biology could potentially bring drugs to market faster with fewer failures. The purpose of this work is to produce cryopreserved adult human small intestinal cells and incorporate those cells into an intestine-hepatocyte co-culture system that will better recapitulate human drug and toxicant metabolism in an in-vitro system. The goals of this proposed project are twofold: 1) Test feasibility of a novl approach for cryopreservation and reanimation of human small intestinal epithelium from either cadaver derived or fresh derived jejunum tissue; 2) Test feasibility of a multi-tissue organ systems incorporating both intestine and liver metabolism to enable a comprehensive benchtop in vitro metabolism model using entirely human- derived products for pharmaceutical efficacy and safety testing as well as industrial chemical safety testing

说明(申请人提供)：进入临床试验的研究药物中只有13%获得批准。其中75%的失败是由于I期和II期临床试验中发现的意想不到的毒性或缺乏疗效。药物在后期开发中的高失败率是临床前动物模型不足以准确预测人类生物学的症状。基于人体器官系统的体外技术有可能克服这些限制，使人类相关生理学能够在药物发现过程中更早地得到研究。换句话说，基于人类生物学而不是动物生物学的更具生理学相关性的体外系统的开发，可能会以更少的失败将药物更快地推向市场。这项工作的目的是生产冷冻保存的成人小肠细胞，并将这些细胞整合到肠-肝细胞共培养系统中，以便在体外系统中更好地概括人类的药物和毒物代谢。这项拟议项目的目标有两个：1)测试从身体或新鲜空肠组织中冷冻保存和复活人类小肠上皮的新方法的可行性；2)测试结合肠道和肝脏代谢的多组织器官系统的可行性，以实现使用完全由人类衍生的产品进行药效和安全性测试以及工业化学安全测试的全面的体外代谢模型。