Dataset Information

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

ABSTRACT:

Background

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.

Objectives

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.

Materials and methods

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.

Results

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.

Conclusions

Overall, our novel PBPK model provides a framework for understanding lymph node penetration of ARVs or future HIV cure therapies.

SUBMITTER: Scholz EMB

PROVIDER: S-EPMC8783597 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Scholz Erin M B EMB Cao Yanguang Y Kashuba Angela D M ADM

The Journal of antimicrobial chemotherapy 20211001 11

<h4>Background</h4>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.<h4>Objectives</h4>To develop customized PBPK models with a novel lymph node compartment, and use these models to des ...[more]

PMID: 34374767

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Project description: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.

Project description:IntroductionHIV reservoirs and infected cells may persist in tissues with low concentrations of antiretrovirals (ARVs). Traditional pharmacology methods cannot assess variability in ARV concentrations within morphologically complex tissues, such as lymph nodes (LNs). We evaluated the distribution of six ARVs into LNs and the proximity of these ARVs to CD4+ T cells and cell-associated RT-SHIV viral RNA.MethodsBetween December 2014 and April 2017, RT-SHIV infected (SHIV+; N = 6) and healthy (SHIV-; N = 6) male rhesus macaques received two selected four-drug combinations of six ARVs over 10 days to attain steady-state conditions. Serial cryosections of axillary LN were analysed by a multimodal imaging approach that combined mass spectrometry imaging (MSI) for ARV disposition, RNAscope in situ hybridization for viral RNA (vRNA) and immunohistochemistry for CD4+ T cell and collagen expression. Spatial relationships across these four imaging domains were investigated by nearest neighbour search on co-registered images using MATLAB.ResultsThrough MSI, ARV-dependent, heterogeneous concentrations were observed in different morphological LN regions, such as the follicles and medullary sinuses. After 5-6 weeks of infection, more limited ARV penetration into LN tissue relative to the blood marker heme was found in SHIV+ animals (SHIV+: 0.7 [0.2-1.4] mm; SHIV-: 1.3 [0.5-1.7] mm), suggesting alterations in the microcirculation. However, we found no detectable increase in collagen deposition. Regimen-wide maps of composite ARV distribution indicated that up to 27% of SHIV+ LN tissue area was not exposed to detectable ARVs. Regions associated with B cell follicles had median 1.15 [0.94-2.69] -fold reduction in areas with measurable drug, though differences were only statistically significant for tenofovir (p = 0.03). Median co-localization of drug with CD4+ target cells and vRNA varied widely by ARV (5.1-100%), but nearest neighbour analysis indicated that up to 10% of target cells and cell-associated vRNA were not directly contiguous to at least one drug at concentrations greater than the IC50 value.ConclusionsOur investigation of the spatial distributions of drug, virus and target cells underscores the influence of location and microenvironment within LN, where a small population of T cells may remain vulnerable to infection and low-level viral replication during suppressive ART.

Dataset Information

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

Background

Objectives

Materials and methods

Results

Conclusions

Publications

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

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