A Continuum Pharmacokinetic Model for Perivascular Drug Transport at the Venous Anastamosis of An Arteriovenous Hemodialysis Graft

Randy Jay Christopherson1, Robert M. Kirby II2, Christi M. Terry3, Alfred K. Cheung3, and Yan-Ting E. Shiu1. (1) Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, (2) Department of Computer Science and the Scientific Computing & Imaging Institute, University of Utah, Salt Lake City, UT 84112, (3) Division of Nephrology, University of Utah, Salt Lake City, UT 84112

Hemodialysis vascular access grafts made of expanded polytetrafluoroethylene (ePTFE) are commonly used in dialysis patients in the U.S. However, they are plagued by stenosis at the venous anastamosis due to the overgrowth of smooth muscle cells and fibroblasts, resulting in neointimal hyperplasia (NH) which causes high failure rates. Previous studies in our lab have investigated the efficacy of preventing stenosis in a porcine model by delivering antiproliferative drugs to the anastamoses of ePTFE grafts from a perivascularly located thermoactive gel (ReGelŪ). However, large animal studies are inherently time consuming and costly. The goal of this study is to develop a continuum pharmokinetic model to predict the concentration profile of perivascularly delivered drugs, thereby decreasing the number of animals required for experimentation and decreasing overall costs. We have developed a finite elements simulation using an idealized geometry in COMSOL multiphysics' transient diffusion application to model this situation. Diffusion is assumed to be isotropic through vessels, graft, and gel, and convection is assumed to be negligible. The effects of various parameters were evaluated in the simulation. These parameters included the initial drug concentration in the gel, diffusion coefficient and reaction rate of the tissue in the perivascular region, drug reaction rate within the venous tissue, and the shape of the gel. Future work will determine whether the assumed first-order kinetics is an appropriate approximation for reaction rates, and the relative importance of the geometry (i.e. idealized vs. realistic) on the diffusion.