Kraft John C, McConnachie Lisa A, Koehn Josefin, Kinman Loren, Collins Carol, Shen Danny D, Collier Ann C, Ho Rodney J Y
aDepartment of Pharmaceutics bDepartment of Medicine cCenter for AIDS Research dDepartment of Bioengineering, University of Washington, Seattle, Washington, USA.
AIDS. 2017 Mar 27;31(6):765-770. doi: 10.1097/QAD.0000000000001405.
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.
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.
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).
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.
本研究旨在确定抗HIV药物替诺福韦（TFV）、洛匹那韦（LPV）和利托那韦（RTV）的脂质稳定纳米混悬液（称为TLC-ART101）联合使用是否能提高并维持淋巴结和血细胞中的细胞内药物水平及暴露量，使其高于血浆中的水平。
给4只猕猴皮下注射单剂量的TLC-ART101。使用经过验证的液相色谱-串联质谱联用（LC-MS/MS）分析法分析血浆以及血液中的单核细胞（PBMCs）和淋巴结中的单核细胞（LNMCs）中的药物浓度。
对于两种活性药物（TFV、LPV），血浆和PBMC中的细胞内药物水平持续超过2周；PBMC中的药物暴露量比血浆中的高3至4倍。TFV和LPV在血浆中的表观终末半衰期（t1/2）分别为65.3和476.9小时，在PBMCs中分别为169.1和151.2小时。在24小时和192小时时，LNMCs中的TFV和LPV药物水平比PBMCs中的高79倍。对PBMC细胞内TFV及其活性代谢产物二磷酸替诺福韦（TFV-DP）的分析表明，总TFV和TFV-DP的细胞内暴露量明显高于口服TFV前药富马酸替诺福韦二吡呋酯（TDF）或替诺福韦艾拉酚胺（TAF）的人类和猕猴，且持续时间更长。
一种简单、可扩展的三药联合脂质稳定纳米混悬液在淋巴结和血液（HIV宿主细胞）以及血浆中的细胞内呈现持续的药物水平。通过适当调整剂量，TLC-ART101可能是一种有效的HIV治疗药物，有可能影响淋巴结中的残留病毒。
