Biodistribution and PK modeling of rat vs. human systems

项目摘要/摘要 我们建议从人类出发构建多器官微生理系统(BoACs) 和大鼠细胞，作为了解暴露在药物或化学品中的物种差异的基础 在评估生物分布的系统中。将在一期和肝脏中构建胃肠道/血脑屏障/神经元BOAC 在第二阶段增加。这项工作将直接测试这种体外模型是否可以准确地复制物种 对已知药物的反应不同。一种基于人类细胞的临床前模型，可以准确预测 人类的反应应该导致更好的决定，无论是接触化学物质还是化学混合物 对人类有害。此外，组织可以交换代谢物和体内的剂量动力学 亲代化合物和代谢物比单一细胞类型暴露于团注时表现得更好 剂量。此外，通过比较急性和慢性影响，它也可以预测临床试验的成功。 用于测定化合物的pK。此外，对来自IPSCs的动物细胞进行比较将使 对它们是否可以替代原始动物细胞的评估。如果成功，这可能会导致 稳定动物模型的细胞来源，减少这些研究所需的动物数量。 LTP的变化将被利用，因为它是神经元活动的功能测量，已知与 记忆和学习的变化。这种神经元模块与芯片上的人系统的集成 包括血脑屏障(BBB)和胃肠道。将肝脏纳入第二阶段还允许对 代谢物对母体化合物的影响。为了构建定义良好的系统，我们将使用 常见的无血清培养基模仿血液的主要特征。希克曼开发了微电极阵列 和悬臂系统，集成在芯片上，允许非侵入性的电子和机械读数 不仅适用于急性测试，也适用于慢性测试。要提高可操作性并实现低容量系统，请 最终的代谢物评估，我们将使用无泵系统(Sung，et al.210)和自含式设备。 我们还将利用微流控分析组件进行快速和灵敏的生物标志物评估。系统 将通过使用CFD进行模拟来建立可接受的营养素和药物消耗范围 以预测系统中的药物浓度分布。我们也将成为合作伙伴 与药物疾病建模和模拟方法专家斯蒂芬·施密特博士共同开发 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 相信这项技术将导致对疗效和成本效益的更准确和更有效的评估 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模型的结合提供了 将直接实验观察与生理上真实的数学模型相结合的机会 这将促进体外数据的外推，以改进对人类反应的预测。

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.