Kinman Loren, Brodie Scott J, Tsai Che Chung, Bui Tot, Larsen Kay, Schmidt Ann, Anderson David, Morton William R, Hu Shiu-Lok, Ho Rodney J Y
Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
J Acquir Immune Defic Syndr. 2003 Dec 1;34(4):387-97. doi: 10.1097/00126334-200312010-00005.
Analysis of indinavir levels in HIV-positive patients indicated that drug concentrations in lymph node mononuclear cells (LNMCs) were about 25-35% of mononuclear cells in blood. To enhance lymphatic delivery of anti-HIV drugs, a novel drug delivery strategy was designed consisting of lipid-associated indinavir (50-80 nm in diameter) complexes in suspension for subcutaneous (SC) injection. Due to the pH-dependent lipophilicity of indinavir, practically all the drug molecules are incorporated into lipid phase when formulated at pH 7.4 and 5:1 lipid-to-drug (m/m) ratio. At pH 5.5, about 20% of drugs were found in lipid-drug complexes. Effects of lipid association on the time course of plasma indinavir concentrations were determined in macaques (Macaca nemestrina) administered with either soluble or lipid-associated formulation of indinavir (10 mg/kg, SC). Results yielded about a 10-fold reduction in peak plasma concentration and a 6-fold enhancement in terminal half-life (t1/2beta = 12 vs. 2 hours). In addition, indinavir concentrations in both peripheral and visceral lymph nodes were 250-2270% higher than plasma (compared with <35% with soluble lipid-free drug administration in humans). Administration of lipid-associated indinavir (20 mg/kg daily) to HIV-2287-infected macaques (at 30-33 weeks after infection) resulted in significantly reduced viral RNA load and increased CD4 T cell number concentrations. Collectively, these data indicate that lipid association greatly enhances delivery of the anti-HIV drug indinavir to lymph nodes at levels that cannot be achieved with soluble drug, provides significant virus load reduction, and could potentially reverse CD4 T cell depletion due to HIV infection.
对HIV阳性患者的茚地那韦水平分析表明，淋巴结单核细胞（LNMCs）中的药物浓度约为血液中单核细胞的25 - 35%。为了增强抗HIV药物的淋巴输送，设计了一种新型药物递送策略，即由悬浮液中的脂质相关茚地那韦（直径50 - 80 nm）复合物进行皮下（SC）注射。由于茚地那韦的pH依赖性亲脂性，当在pH 7.4和脂质与药物比例为5:1（m/m）时配制，几乎所有药物分子都被纳入脂质相。在pH 5.5时，约20%的药物存在于脂质 - 药物复合物中。在用可溶性或脂质相关制剂的茚地那韦（10 mg/kg，SC）给药的猕猴（食蟹猴）中，测定了脂质结合对血浆茚地那韦浓度时间进程的影响。结果显示血浆峰浓度降低了约10倍，终末半衰期延长了6倍（t1/2β = 12小时对2小时）。此外，外周和内脏淋巴结中的茚地那韦浓度比血浆高250 - 2270%（相比之下，人类使用无脂质的可溶性药物给药时该比例<35%）。对感染HIV - 2287的猕猴（感染后30 - 33周）每日给予脂质相关茚地那韦（20 mg/kg），导致病毒RNA载量显著降低，CD4 T细胞数量浓度增加。总体而言，这些数据表明脂质结合极大地增强了抗HIV药物茚地那韦向淋巴结的递送，达到了可溶性药物无法实现的水平，显著降低了病毒载量，并可能逆转因HIV感染导致的CD4 T细胞耗竭。
