A cross-species comparison of antiretroviral penetration into lymph nodes using novel physiologically based pharmacokinetic models.

Abstract

Investigating antiretroviral (ARV) penetration and pharmacology in lymph nodes is crucial to understanding mechanisms of HIV persistence in tissue, but sampling these tissues in humans is invasive and costly. Physiologically based pharmacokinetic (PBPK) modelling is a non-invasive solution for understanding lymph node penetration of ARVs across multiple species. To develop customized PBPK models with a novel lymph node compartment, and use these models to describe the distribution of three ARVs-tenofovir, emtricitabine and efavirenz-into the plasma and lymph nodes of non-human primates (NHPs) and humans. In this analysis, we utilized standard monkey and human PBPK models in PK-Sim, and added a novel lymph node compartment using MoBi. We used these models to describe the distribution of tenofovir, emtricitabine and efavirenz into NHP and human plasma and lymph nodes, and compared model-predicted versus observed AUC and Cmax. For all three ARVs, population simulations using the base and final models reasonably characterized observed plasma and tissue data in NHPs and humans, with predicted/observed AUC and Cmax ratios within 0.7-2.0. Overall, our novel PBPK model provides a framework for understanding lymph node penetration of ARVs or future HIV cure therapies.