Biodistribution and PK modeling of rat vs. human systems

大鼠与人体系统的生物分布和 PK 建模

• 批准号: 10359139
• 负责人: MICHAEL L SHULER
• 金额: $ 78.94万
• 依托单位: HESPEROS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359139
• 关键词: Academia; Acute; Address; Adult; Animal Model; Animal Sources; Animals; Attention; Biodistribution; Biological Markers; Blood; Blood - brain barrier anatomy; Bolus Infusion; Brain; Cardiac; Cell Survival; Cells; Cellular Morphology; Chemicals; Chronic; Clinical; Clinical Trials; Consumption; Data; Development; Devices; Disease; Disease model; Dose; Drug Delivery Systems; Drug Kinetics; Drug Transport; Drug or Chemical; Endothelium; Evaluation; Exposure to; Failure; Female; Gastrointestinal tract structure; Generations; Goals; Grant; Health; Human; In Vitro; Industry; Intellectual Property; Intravenous; Investigation; Laboratories; Lead; Learning; Literature; Liver; Long-Term Potentiation; Measurement; Mechanics; Memory; Metabolism; Microelectrodes; Microfluidics; Modeling; Muscle; Neonatal; Neurons; Oral; Organ; Organ Model; Outcome; Parents; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacotherapy; Phase; Phenotype; Physiological; Physiology; Pre-Clinical Model; Preclinical Testing; Property; Publishing; Qi; Rare Diseases; Rattus; Research; Route; Serum; Services; Site; Small Business Innovation Research Grant; System; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Treatment Protocols; Underserved Population; Vision; Work; absorption; aged; base; biological systems; body on a chip; body system; cantilever; cell type; cost effective; drug metabolism; efficacy evaluation; experience; experimental study; human data; human model; improved; in vitro Model; in vivo; induced pluripotent stem cell; interest; male; mathematical model; microphysiology system; models and simulation; nutrient metabolism; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; physiologically based pharmacokinetics; pre-clinical; programs; response; shear stress; species difference; success; tool

Project Summary/Abstract We propose to construct multi organ microphysiological systems (“Body-on-a-Chip” or BoaCs) from human and rat cells to use as a basis to understand species differences in response to exposure to drugs or chemicals in a system to evaluate biodistribution. A GI tract/BBB/neuronal BoaC will be constructed in Phase I and liver added in Phase II. This work will directly test whether such in vitro models can accurately reproduce species differences in response to known drugs. A preclinical model based on human cells that can accurately predict human response should lead to better decisions on whether exposure to a chemical or chemical mixture will be harmful to humans. Also, the tissues can exchange metabolites and the dose dynamics in the body of both parental compounds and metabolites are better represented than when a single cell type is exposed to a bolus dose. In addition, by comparing acute to chronic effects it will enable prediction on clinical trial success as well for determining PK of the compounds. In addition, the comparison of animal cells derived from iPSCs will enable the assessment of whether they can be substituted for primary animal cells. If successful, this could lead to stable cell sources for the animal models and reduce the number of animals needed for these studies. Changes in LTP will be utilized as it is a functional measurement of neuronal activity known to correlate with changes in memory and learning. The integration of this neuronal module with a human-on-a-chip system that includes a blood-brain-barrier (BBB) and GI tract. Inclusion of the liver in Phase II also allows investigation of the effect of metabolites in addition to the parent compound. To construct a well defined system we will use a common serum free medium which mimics key features of blood. Hickman has developed microelectrode arrays and cantilever systems that are integrated on chip that allow for noninvasive electronic and mechanical readouts for not only acute but also chronic tests as well. To improve operability and enable a low volume system for eventual metabolite evaluation, we will use a pumpless system (Sung, et al. 210) and self contained devices. We will also utilize microfluidic analytical components for rapid and sensitive biomarker assessment. The system will be modeled by simulation using CFD to establish acceptable ranges for consumption of nutrients and drug metabolism as well as shear stress and to predict drug concentration profiles in the system. We also will partner with Dr. Stephan Schmidt, an expert in drug-disease modeling and simulation approaches, to develop pharmacokinetic/pharmacodynamic (PBPK/PD) models to relate the in vitro studies to clinical outcomes. We believe that this technique will lead to more accurate and cost-effective assessment of the efficacy and toxicological potential of drugs chemicals or chemical mixtures and this approach will have a major impact on improving human health. Further, the combination of a multi-organ in vitro model with PBPK/PD modeling offers an opportunity to integrate direct experimental observations with a physiologically realistic mathematical model which will facilitate extrapolation of in vitro data to improved prediction of human response.

项目摘要/摘要 我们建议从人类构建多有机微生物生理系统（“片上的身体”或BOAC） 和大鼠细胞用作理解对药物或化学物质暴露的物种差异的基础 在评估生物分布的系统中。将在I和肝脏中构建GI区/BBB/神经元BOAC 在第二阶段中添加。这项工作将直接测试这种体外模型是否可以准确再现物种 对已知药物的响应差异。基于人类细胞的临床前模型，可以准确预测 人类反应应该可以更好地决定暴露于化学或化学混合物 对人类有害。此外，组织可以交换代谢物和两者体内的剂量动力学 父母化合物和代谢物比单个细胞类型暴露于推注时更好地表示 剂量。另外，通过将急性与慢性影响进行比较，它也可以预测临床试验成功 用于确定化合物的PK。另外，从IPSC衍生的动物细胞的比较将启用 评估它们是否可以代替原代动物细胞。如果成功，这可能会导致 动物模型的稳定细胞源，并减少这些研究所需的动物数量。 LTP的变化将被利用，因为它是对已知与之相关的神经元活性的功能测量 记忆和学习的变化。该神经元模块与人类对芯片系统的整合，该模块的整合 包括血脑屏障（BBB）和胃肠道。将肝脏纳入第二阶段还允许研究 除母体外，代谢物的作用。要构建一个定义明确的系统，我们将使用 常见的无血清培养基，模仿血液的关键特征。希克曼已经开发了微电极阵列 集成在芯片上的悬臂系统，可以进行无创电子和机械读数 不仅急性，而且还进行慢性测试。提高操作性并启用低容量系统 最终的代谢物评估，我们将使用Pumpless系统（Sung等，210）和自包含的设备。 我们还将利用微流体分析成分进行快速和敏感的生物标志物评估。系统 将通过使用CFD进行模拟来建立模拟，以建立可接受的营养和药物的范围 代谢以及剪切应力并预测系统中的药物浓度谱。我们还将合作 与药物疾病建模和模拟方法专家斯蒂芬·施密特（Stephan Schmidt）博士一起开发 药代动力学/药效学（PBPK/PD）模型将体外研究与临床结局相关联。我们 相信这项技术将导致对效率的更准确和成本效益的评估 药物化学物质或化学混合物的毒理学潜力，这种方法将对 改善人类健康。此外，多器官在体外模型与PBPK/PD建模的组合提供 将直接实验观测与物理现实的数学模型整合到直接实验观察的机会 这将有助于推断体外数据以改善人类反应的预测。