Local pharmacokinetics of stent-based drug delivery

Stent-based delivery of cardiovascular therapeutics produces a wide range of effects, from complete reduction of restenosis to exacerbation of disease. This thesis investigates how and why drugs of similar potency in cell culture have such drastically different outcomes in clinical trials. Our central hypothesis is that local drug concentration variations in the target tissue, on the length scale of single cells, can affect the global outcome of a particular therapeutic and mode of delivery. In a series of studies we elucidated the role of local pharmacokinetics in stent-based drug delivery. We measured drug transport parameters in different arterial beds, and defined the role of ultrastructure, tissue composition and organization in shaping local drug distribution. We mapped and modeled the drug distribution in the arterial wall following local delivery and characterized how transport properties and stent geometry affect delivery efficiency. Finally, we tracked intercellular signaling in tissue during sustained drug administration, and examined the correlation of the distribution of drug to the distribution of biologic response. Our findings suggest that the interplay of local physiological transport forces, drug physicochemical traits and arterial ultrastructure can generate large variations in local drug concentrations, resulting in regions of the arterial wall with drug levels far outside the therapeutic window. These results imply that local pharmacokinetics play a critical role in the clinical efficacy of locally delivered drugs, and must be a consideration in the rational design of stent-based delivery devices.