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/PD characteristics associated with poor lymphoid penetration include high cellular uptake rates and low intracellular half-lives. To determine whether this exclusion might lead to ongoing replication, target CD4+ T cell, infected CD4+ T cell, free virus, and intracellular IC50 values of anti-retroviral drugs were incorporated into the model. Notably, for median estimates of PK/PD parameters and lobule diameters consistent with low to moderate inflammation, the model predicts no ongoing viral replication, despite substantial exclusion of the drugs from the lymphoid site. Monte-Carlo studies drawn from the prior distributions of the PK/PD parameters predicts increases in site-specific HIV replication in a small fraction of the patient population for lobule diameters greater than 0.2 mm; this fraction increases as the site diameter/ inflammation level increases. The model shows that cART consisting of two nRTIs and one PI is the most likely treatment combination to support formation of a sanctuary site, a finding that is consistent with clinical observations.

The Lymph Node Reservoir: Physiology, HIV Infection, and Antiretroviral Therapy

“…Furthermore, inflammation and fibrosis can alter the structure and size of the lymph node, disrupting normal pressure gradients and drug perfusion patterns throughout the tissue. 26,78,79 Jagarapu et al found an association between increased lymphoid lobule size and drug exclusion from the center of the lobule. 79 This is consistent with Jafarnejad et al's findings that lymphadenopathy during inflammation and/or viral infection can cause higher pressure in the lymph node and result in increased fluid flow back into blood vessels.…”

“…26,78,79 Jagarapu et al found an association between increased lymphoid lobule size and drug exclusion from the center of the lobule. 79 This is consistent with Jafarnejad et al's findings that lymphadenopathy during inflammation and/or viral infection can cause higher pressure in the lymph node and result in increased fluid flow back into blood vessels. 26,80 Quantifying ARV concentrations and distribution in the lymph node Table 3 provides several examples of ARV concentrations quantified in lymph node tissue or isolated lymph node mononuclear cells (LNMCs).…”

“…distribution in the lymph node, because these drugs have the least favorable physicochemical properties for free drug perfusion (low molecular weight, low lipophilicity, and fast diffusion back into blood) and likely distribute most effectively through cell trafficking. Furthermore, inflammation and fibrosis can alter the structure and size of the lymph node, disrupting normal pressure gradients and drug perfusion patterns throughout the tissue 26,78,79 . Jagarapu et al .…”

Pharmacology of HIV Cure: Site of Action

“…38 These lobules receive blood flow from specialized postcapillary venous channels known as high endothelial venules that facilitate the crossover from blood to LN parenchyma. 38 They are of particular interest due to the high density of cellular phenotypes that can be latently infected with HIV as well as previous identification of HIV persistence. Horiike et al utilized an NHP model that was chronically infected with SIV and suppressed on ART, to explore viral rebound after ART cessation.…”

“…40 LNs are pharmacologically unique since xenobiotics enter a lymphoid follicle (the primary point of entry into a LN lobule) through high endothelial venules vs. "traditional" blood flow as seen with other organs. 38 Like the CsfPR, a key measure of ART distribution into peripheral tissues is the tissue-to-plasma penetration ratio (TPR), which is the concentration of ART observed in a particular tissue normalized to that observed in the plasma at either a single matched moment in time or averaged over a defined time frame. A ratio of 1 indicates that the tissue exposure is equivalent to that of the blood.…”