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Pharmacokinetic-Pharmacodynamic Model On A Chip For Testing Toxicity Of Chemotherapeutic Agents
|dc.description.abstract||Human response to drugs and environmental chemicals is often dramatically different from predictions made by conventional cell-based assays. Current in vitro methods for testing drug toxicity use a single cell type in a static culture environment, treated with a bolus dose. Such experiments do not capture the complex, dynamic response of the body to drug absorption, distribution, metabolism and excretion (ADME). Integrated pharmacokinetic-pharmacodynamic (PK-PD) models allow prediction of pharmacological outcome from a give dosage, but have limitations in building realistic models. A micro cell culture analog (mu-CCA) is a microfluidic device based on a physiologically-based pharmacokinetic (PBPK) model, with multiple chambers each representing an organ or tissue on a silicon chip, with these chambers connected to emulate the blood circulation. This thesis work describes the combined approach of a PK-PD modeling and a mu-CCA platform, for testing the toxicity of chemotherapeutic agents. A PK-PD model was developed to predict tumor growth in a rat, treated with the chemotherapeutic agent, Tegafur. Various dosing scenarios and the effect of metabolizing enzyme levels were tested. As an experimental approach, the mu-CCA was improved in design, to accommodate 3-D hydrogel cell cultures and to enable a long-term operation. Using the mu-CCA, metabolism-dependent toxicity of Tegafur was observed. A PK-PD model for a mu-CCA was developed, and differential responses of three cell lines (representing the liver, tumor, and marrow) to the drugs in static and dynamic conditions were analyzed. A major challenge in developing microfluidic systems is prevention of bubble formation. A microscale bubble trap was developed, and it was demonstrated that the presence of a bubble trap significantly alleviated the bubble interference. To address the issue of detection and analysis in a microfluidic device, an in situ, fluorescence optical detection system was developed and integrated with a mu-CCA, and a real-time detection of cell viability and metabolic activity was demonstrated. This thesis work demonstrates the use of a microfluidic device, mu-CCA for a pharmacokinetic-based drug toxicity study and its combination with a mathematical modeling for a quantitative analysis of cell death kinetics. We envision that the combined approach will be useful in improving the productivity of drug development process by supplementing animal and human studies.||en_US|
|dc.title||Pharmacokinetic-Pharmacodynamic Model On A Chip For Testing Toxicity Of Chemotherapeutic Agents||en_US|
|dc.type||dissertation or thesis||en_US|