Speaker
Description
Protein-unbound antiretroviral (ARV) drugs in the plasma may either diffuse across the walls of high endothelial venules (HEVs) into the lymph node (LN) parenchyma or be taken up by lymphocytes (naïve T cells) in the bloodstream and transported into the lymph node through cell migration via HEVs. To explore the relative contributions of free and cell-mediated drug trafficking, our collaborators have performed experiments in which lymphocyte traffic into the LN is blocked by a functional antibody. In this work, we develop a pharmacokinetic model for efavirenz (EFV) that contains four compartments: Plasma (bound & unbound), peripheral blood mono-nuclear cells (PBMC), LN interstitial fluid (bound & unbound), and LN intracellular region, while also tracking the changes in total interstitial fluid volume as a result of blocking lymphocyte ingress. Non-linear differential equations were employed to describe the transport of EFV between these compartments. The model predicts that blocking lymphocyte entry into the LN leads to an increase in extracellular volume over time and substantially increases the total drug concentration in the LN compared to the case where normal lymphocyte entry is maintained. Additionally, our analysis reveals that obstructing the entry of cells into the LN increases intracellular drug concentration in the LN, but it has no significant impact on blood intracellular drug concentration. These results are consistent with experimental data from our collaborating lab. In conclusion, this mathematical model explains the counterintuitive finding that blocking the entry of cells into the LN results in an increase in the drug concentration within the LN, emphasizing the importance of considering extracellular volume dynamics in ARV drug transport studies.
