An Integrated Spatial Dynamics-Pharmacokinetic Model Explaining Poor Penetration of Anti-retroviral Drugs in Lymph Nodes
Abstract
Although combined anti-retroviral therapy (cART) suppresses plasma HIV viremia below the limit of detection in a majority of HIV patients, evidence is emerging that the distribution of the anti-retroviral drugs is heterogeneous in tissue. Clinical studies measuring antiretroviral drug concentrations in lymph nodes (LNs) revealed lower concentrations compared to peripheral blood levels suggesting poor drug penetration properties. Our current study is an attempt to understand this poor anti-retroviral drug penetration inside lymph node lobules through integrating known pharmacokinetic and pharmacodynamic (PK/PD) parameters of the anti-retroviral drugs into a spatial model of reaction and transport dynamics within a solid lymph node lobule. Simulated drug penetration values were compared against experimental results whenever available or matched with data that is available for other drugs in a similar class. Our integrated spatial dynamics pharmacokinetic model reproduced the experimentally observed exclusion of antivirals from lymphoid sites. The strongest predictor of drug exclusion from the lymphoid lobule, independent of drug class, was lobule size; large lobules (high inflammation) exhibited high levels of drug exclusion. PK/...Continue Reading
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