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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DOI：
10.1097/qad.0000000000001405
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发表时间：
2017-03-27
期刊：
影响因子：
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通讯作者：
Ho RJ
中科院分区：
文献类型：
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作者：
Kraft JC;McConnachie LA;Koehn J;Kinman L;Collins C;Shen DD;Collier AC;Ho RJ
本研究的目的是确定抗HIV药物-替诺福韦（TFV），洛匹那韦（LPV）和利托那韦（RTV）-在脂质稳定的纳米混悬液（称为TLC-ART 101）中的组合是否可以增强和维持淋巴结和血细胞中的细胞内药物水平和暴露高于血浆中的水平。四只猕猴皮下给予单剂量的TLC-ART 101。使用经验证的LC-MS/MS联合分析法分析血浆和血液单核细胞（PBMC）和淋巴结（LNMC）中的药物浓度。对于两种活性药物（TFV、LPV），血浆和PBMC细胞内药物水平持续超过2周; PBMC药物暴露量是血浆药物暴露量的3 - 4倍。血浆中TFV和LPV的表观终末半衰期（t1/2）分别为65.3和476.9 h， PBMC中分别为169.1和151.2 h。 在24和192小时，LNMCs中的TFV和LPV药物水平比PBMC中的药物水平高79倍。 PBMC细胞内TFV及其活性代谢物TFV-二磷酸（TFV-DP）的分析表明，总TFV和TFV-DP的细胞内暴露量显著高于口服TFV前药富马酸替诺福韦二异山梨酯（TDF）或替诺福韦艾拉酚胺（TAF）给药的人和猕猴，并且持续时间更长。一个简单的，可扩展的三种药物组合，脂质稳定的纳米混悬液在淋巴结和血液（HIV宿主细胞）的细胞和血浆中表现出持久的药物水平。通过适当的剂量调整，TLC-ART 101可能是一种有用的HIV治疗方法，有可能影响淋巴结中的残留病毒。
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.