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Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma.

Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma.
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Kraft JC, McConnachie LA, Koehn J, Kinman L, Collins C, Shen DD, Collier AC, Ho RJ,


Kraft JC, McConnachie LA, Koehn J, Kinman L, Collins C, Shen DD, Collier AC, Ho RJ, (click to view)

Kraft JC, McConnachie LA, Koehn J, Kinman L, Collins C, Shen DD, Collier AC, Ho RJ,

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AIDS (London, England) 31(6) 765-770 doi 10.1097/QAD.0000000000001405

Abstract
OBJECTIVE
The aim of the present study was to determine whether a combination of anti-HIV drugs – tenofovir (TFV), lopinavir (LPV) and ritonavir (RTV) – in a lipid-stabilized nanosuspension (called TLC-ART101) could enhance and sustain intracellular drug levels and exposures in lymph node and blood cells above those in plasma.

DESIGN
Four macaques were given a single dose of TLC-ART101 subcutaneously. Drug concentrations in plasma and mononuclear cells of the blood (PBMCs) and lymph nodes (LNMCs) were analysed using a validated combination LC-MS/MS assay.

RESULTS
For the two active drugs (TFV, LPV), plasma and PBMC intracellular drug levels persisted for over 2 weeks; PBMC drug exposures were three- to four-fold higher than those in plasma. Apparent terminal half-lives (t1/2) of TFV and LPV were 65.3 and 476.9 h in plasma, and 169.1 and 151.2 h in PBMCs. At 24 and 192 h, TFV and LPV drug levels in LNMCs were up to 79-fold higher than those in PBMCs. Analysis of PBMC intracellular TFV and its active metabolite TFV-diphosphate (TFV-DP) indicated that intracellular exposures of total TFV and TFV-DP were markedly higher and persisted longer than in humans and macaques dosed with oral TFV prodrugs, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF).

CONCLUSIONS
A simple, scalable three-drug combination, lipid-stabilized nanosuspension exhibited persistent drug levels in cells of lymph nodes and the blood (HIV host cells) and in plasma. With appropriate dose adjustment, TLC-ART101 may be a useful HIV treatment with a potential to impact residual virus in lymph nodes.

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