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: 10079898
• 负责人: MICHAEL L SHULER
• 金额: $ 22.63万
• 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 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079898
• 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; 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.

项目概要/摘要 我们建议构建人体多器官微生理系统（“芯片上的身体”或BoaCs） 和大鼠细胞作为了解药物或化学品暴露反应的物种差异的基础 在评估生物分布的系统中。 I期将构建胃肠道/BBB/神经元BoaC和肝脏 在第二阶段添加。这项工作将直接测试此类体外模型是否能够准确地繁殖物种 对已知药物的反应存在差异。基于人体细胞的可准确预测的临床前模型 人类的反应应该导致更好的决定是否接触化学品或化学混合物会受到影响。 对人类有害。此外，组织可以交换代谢物和体内的剂量动态 与单一细胞类型暴露于推注相比，母体化合物和代谢物得到更好的体现 剂量。此外，通过比较急性和慢性影响，还可以预测临床试验的成功 用于确定化合物的 PK。此外，对源自 iPSC 的动物细胞进行比较将使 评估它们是否可以替代原代动物细胞。如果成功的话，这可能会导致 为动物模型提供稳定的细胞来源，并减少这些研究所需的动物数量。 将利用 LTP 的变化，因为它是已知与相关的神经元活动的功能测量 记忆和学习的变化。该神经元模块与人类芯片系统的集成 包括血脑屏障 (BBB) 和胃肠道。将肝脏纳入第二阶段还可以研究 除母体化合物外，代谢物的影响。为了构建一个定义明确的系统，我们将使用 模拟血液主要特征的常见无血清培养基。希克曼开发出微电极阵列 和集成在芯片上的悬臂系统，可实现非侵入式电子和机械读数 不仅适用于急性测试，也适用于慢性测试。提高可操作性并实现低容量系统 最终的代谢物评估，我们将使用无泵系统（Sung 等人，210）和独立设备。 我们还将利用微流体分析组件进行快速、灵敏的生物标志物评估。系统 将使用 CFD 进行模拟建模，以确定营养素和药物消耗的可接受范围 代谢以及剪切应力并预测系统中的药物浓度分布。我们也将合作 与药物疾病建模和模拟方法专家 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果联系起来。我们 相信这项技术将带来更准确和更具成本效益的疗效评估 药物化学品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，多器官体外模型与 PBPK/PD 建模的结合提供了 将直接实验观察与生理学现实数学模型相结合的机会 这将有助于体外数据的外推，以改进对人类反应的预测。