Biodistribution and PK modeling of rat vs. human systems

Project Summary/AbstractWe 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.NarrativeHesperos will construct very small multi-organ systems with brain, liver, GI tract and blood brain barrier from human and rat cells to use as a basis to understand species differences in response to exposure to drugs or chemicals. This work will directly test whether such in vitro models can accurately reproduce species differences in biodistribution in response to known compounds. A preclinical model based on human cells that can accurately predict human response that is validated against an animal version should lead to better decisions on whether exposure to a chemical or chemical mixture will be harmful to humans and lessen the reliance on in vivo experiments for the evaluations.