PhD candidate University of Delaware Elkton, Maryland, United States
Introduction: Antiretroviral (ARV) drugs have been significantly successful in treating HIV-infected patients throughout the past decade. Recent studies, however, have shown that ARVs distribute heterogeneously in tissues such as the lymph nodes (LNs), basically not penetrating sufficiently to suppress the virus within the tissue. We have previously developed a mathematical model that solves pharmacokinetic (PK) reactions and spatial diffusion dynamics on a fully reconstructed 3D geometry of a murine LN. The simulation outputs of the model reproduce the spatial patterns of ARV distributions that have been formerly observed in LNs using direct imaging techniques. The transport mechanisms into the LN are considered to be diffusion-like and via blood or fluid lymph only, either as free drug or as intercellular cargo via the T-cells. In this study, we have used this model and simulation pipeline to perform a local sensitivity analysis in order to determine the model’s sensitivity to all the transport rates from the different mechanisms that transport the drug into the LNs. A clear understanding of the mechanisms of drug exclusion in tissues such as the LN can contribute to the development of more effective drugs not only targeting HIV therapy but also for the treatment of numerous conditions including cancer.
Materials and
Methods: In this study, a local sensitivity analysis was performed on the existing model of the protease inhibitor (PI) drugs class from the ARVs to determine the effects and sensitivities of different drug transport mechanisms into the LN. We used the models developed by Dixit et.al. [1] to solve the pharmacokinetics of a typical protease inhibitor drug (e.g., Ritonavir) on an accurate 3D geometry of a murine LN, derived from a pipeline comprised of high-resolution confocal imaging, segmentation, and volumetric anatomical reconstruction. The model contains LN lobule(s), and the vasculature within the LN. The geometries were imported into MATLAB and tetrahedral meshing was applied (Fig 1). Transport of ARV drugs between the blood and the lobule and within the lobule was assumed to follow diffusion-like properties. The coefficients for diffusion were estimated using Einstein-Stokes equations. As mentioned above, the four dominating mechanisms of drug transport into the LN were calculated and inserted into the equations of the model. The reaction-diffusion equations of the PI drug family were then solved using a Finite Volume Method on the geometry described, and the relative local sensitivities of the model to each transport rate were calculated (Fig 2).
Results, Conclusions, and Discussions: Our results show that the drug concentrations have the highest sensitivity to transport rates of extracellular transport from the LN to lymph and from the LN to blood, more towards the end of the simulation days (day 2 and day 3.5). These results are consistent with previously mentioned/simulated drug distribution patterns in the LN. We have developed a local sensitivity analysis pipeline to study the effects of drug transport rates on ARV drugs. This method can provide a valuable tool for designing more penetrable ARVs and contribute to a more potent drug delivery, as well as be a valuable tool in drug discovery and design of improved treatments for HIV and by extension other conditions that involve drug exclusion from lymphoid tissues.
Acknowledgements (Optional):
References:
[1] Narendra M Dixit and Alan S Perelson. Complex patterns of viral load decay under antiretroviral therapy: influence of pharmacokinetics and intracellular delay. Journal of Theoretical Biology, 226(1):95–109, 2004.
