Biodistribution and PK modeling of rat vs. human systems

项目总结/摘要 我们提出了构建人体多器官微生理系统（Body-on-a-Chip，BoaCs）的设想 和大鼠细胞作为基础，以了解物种对药物或化学品暴露的反应差异 来评估生物分布。将在I期和肝脏中构建GI道/BBB/神经元BoaC 在第二阶段添加。这项工作将直接测试这样的体外模型是否能够准确地繁殖物种 对已知药物的反应差异。基于人类细胞的临床前模型，可以准确预测 人类的反应应导致更好地决定是否接触化学品或化学混合物， 对人类有害。此外，组织可以交换代谢物和剂量动力学在体内的两个 亲本化合物和代谢物比当单个细胞类型暴露于推注时更好地呈现 次给药结束此外，通过比较急性和慢性效应，还可以预测临床试验的成功率 用于测定化合物的PK。此外，对来源于iPSC的动物细胞的比较将使 评估它们是否可以替代原代动物细胞。如果成功，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。 将使用LTP的变化，因为它是已知与以下相关的神经元活动的功能测量： 记忆和学习的变化。这种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II期研究还允许研究 除母体化合物外，代谢产物的作用。为了构建一个定义良好的系统，我们将使用 模拟血液关键特征的普通无血清培养基。希克曼开发了微电极阵列 以及集成在芯片上的悬臂系统，其允许非侵入式电子和机械读数 不仅适用于急性试验，也适用于慢性试验。为了提高可操作性并实现低容量系统， 最终的代谢物评价，我们将使用无泵系统（Sung等人，210）和独立装置。 我们还将利用微流体分析组件进行快速和灵敏的生物标志物评估。系统 将使用CFD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。我们还将与 与药物疾病建模和模拟方法专家Stephan施密特博士合作， 药代动力学/药效学（PBPK/PD）模型，以将体外研究与临床结局联系起来。我们 我相信，这种技术将导致更准确和成本效益的疗效评估， 毒品、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建模的组合提供了 将直接实验观察与生理学上现实的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体反应的预测。

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.