Abstract
In a “kick and kill” strategy for human immunodeficiency virus (HIV) eradication, protective concentrations of antiretrovirals (ARVs) in the lymph node are important to prevent vulnerable cells from further HIV infection. However, the factors responsible for drug distribution and concentration into these tissues are largely unknown. Although humanized mice and nonhuman primates (NHPs) are crucial to HIV research, ARV tissue pharmacology has not been well characterized across species. This study investigated the influence of drug transporter expression, viral infection, and sex on ARV penetration within lymph nodes of animal models and humans. Six ARVs were dosed for 10 days in humanized mice and NHPs. Plasma and lymph nodes were collected at necropsy, 24 hours after the last dose. Human lymph node tissue and plasma from deceased patients were collected from tissue banks. ARV, active metabolite, and endogenous nucleotide concentrations were measured by liquid chromatography-tandem mass spectrometry, and drug transporter expression was measured using quantitative polymerase chain reaction and quantitative targeted absolute proteomics. In NHPs and humans, lymph node ARV concentrations were greater than or equal to plasma, and tenofovir diphosphate/ deoxyadenosine triphosphate concentration ratios achieved efficacy targets in lymph nodes from all three species. There was no effect of infection or sex on ARV concentrations. Low drug transporter expression existed in lymph nodes from all species, and no predictive relationships were found between transporter gene/protein expression and ARV penetration. Overall, common preclinical models of HIV infection were well suited to predict human ARV exposure in lymph nodes, and low transporter expression suggests primarily passive drug distribution in these tissues.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 360-368 |
| Number of pages | 9 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 370 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Molecular Medicine
- Pharmacology
Cite this
Antiretroviral drug concentrations in lymph nodes : A cross-species comparison of the effect of drug transporter expression, viral infection, and sex in humanized mice, nonhuman primates, and humans. / Burgunder, Erin; Fallon, John K.; White, Nicole; Schauer, Amanda P.; Sykes, Craig; Remling-Mulder, Leila; Kovarova, Martina; Adamson, Lourdes; Luciw, Paul A; Victor Garcia, J.; Akkina, Ramesh; Smith, Philip C.; Kashuba, Angela D.M.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 370, No. 3, 01.01.2019, p. 360-368.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Antiretroviral drug concentrations in lymph nodes
T2 - A cross-species comparison of the effect of drug transporter expression, viral infection, and sex in humanized mice, nonhuman primates, and humans
AU - Burgunder, Erin
AU - Fallon, John K.
AU - White, Nicole
AU - Schauer, Amanda P.
AU - Sykes, Craig
AU - Remling-Mulder, Leila
AU - Kovarova, Martina
AU - Adamson, Lourdes
AU - Luciw, Paul A
AU - Victor Garcia, J.
AU - Akkina, Ramesh
AU - Smith, Philip C.
AU - Kashuba, Angela D.M.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - In a “kick and kill” strategy for human immunodeficiency virus (HIV) eradication, protective concentrations of antiretrovirals (ARVs) in the lymph node are important to prevent vulnerable cells from further HIV infection. However, the factors responsible for drug distribution and concentration into these tissues are largely unknown. Although humanized mice and nonhuman primates (NHPs) are crucial to HIV research, ARV tissue pharmacology has not been well characterized across species. This study investigated the influence of drug transporter expression, viral infection, and sex on ARV penetration within lymph nodes of animal models and humans. Six ARVs were dosed for 10 days in humanized mice and NHPs. Plasma and lymph nodes were collected at necropsy, 24 hours after the last dose. Human lymph node tissue and plasma from deceased patients were collected from tissue banks. ARV, active metabolite, and endogenous nucleotide concentrations were measured by liquid chromatography-tandem mass spectrometry, and drug transporter expression was measured using quantitative polymerase chain reaction and quantitative targeted absolute proteomics. In NHPs and humans, lymph node ARV concentrations were greater than or equal to plasma, and tenofovir diphosphate/ deoxyadenosine triphosphate concentration ratios achieved efficacy targets in lymph nodes from all three species. There was no effect of infection or sex on ARV concentrations. Low drug transporter expression existed in lymph nodes from all species, and no predictive relationships were found between transporter gene/protein expression and ARV penetration. Overall, common preclinical models of HIV infection were well suited to predict human ARV exposure in lymph nodes, and low transporter expression suggests primarily passive drug distribution in these tissues.
AB - In a “kick and kill” strategy for human immunodeficiency virus (HIV) eradication, protective concentrations of antiretrovirals (ARVs) in the lymph node are important to prevent vulnerable cells from further HIV infection. However, the factors responsible for drug distribution and concentration into these tissues are largely unknown. Although humanized mice and nonhuman primates (NHPs) are crucial to HIV research, ARV tissue pharmacology has not been well characterized across species. This study investigated the influence of drug transporter expression, viral infection, and sex on ARV penetration within lymph nodes of animal models and humans. Six ARVs were dosed for 10 days in humanized mice and NHPs. Plasma and lymph nodes were collected at necropsy, 24 hours after the last dose. Human lymph node tissue and plasma from deceased patients were collected from tissue banks. ARV, active metabolite, and endogenous nucleotide concentrations were measured by liquid chromatography-tandem mass spectrometry, and drug transporter expression was measured using quantitative polymerase chain reaction and quantitative targeted absolute proteomics. In NHPs and humans, lymph node ARV concentrations were greater than or equal to plasma, and tenofovir diphosphate/ deoxyadenosine triphosphate concentration ratios achieved efficacy targets in lymph nodes from all three species. There was no effect of infection or sex on ARV concentrations. Low drug transporter expression existed in lymph nodes from all species, and no predictive relationships were found between transporter gene/protein expression and ARV penetration. Overall, common preclinical models of HIV infection were well suited to predict human ARV exposure in lymph nodes, and low transporter expression suggests primarily passive drug distribution in these tissues.
UR - http://www.scopus.com/inward/record.url?scp=85071354671&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071354671&partnerID=8YFLogxK
U2 - 10.1124/jpet.119.259150
DO - 10.1124/jpet.119.259150
M3 - Article
C2 - 31235531
AN - SCOPUS:85071354671
VL - 370
SP - 360
EP - 368
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -