Department of Pharmaceutics, University of Washington, Seattle, Washington 98195.
Department of Medicine, University of Washington, Seattle, Washington 98195; Center for AIDS Research, University of Washington, Seattle, Washington 98195.
J Pharm Sci. 2018 Jul;107(7):1787-1790. doi: 10.1016/j.xphs.2018.03.005. Epub 2018 Mar 13.
Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography-tandem mass spectrometry. Plasma and PBMC levels of the active drugs (LPV, TFV, and 3TC) were sustained for 5 weeks; PBMC exposures to LPV, ritonavir, and 3TC were 12-, 16-, 42-fold higher than those in plasma. Apparent T of LPV, TFV, and 3TC were 219.1, 63.1, and 136.3 h in plasma; 1045.7, 105.9, and 127.7 h in PBMCs. At day 8, LPV, TFV, and 3TC levels in LNMCs were 4.1-, 5.0-, and 1.9-fold higher than in those in PBMCs and much higher than in plasma. Therefore, 1 dose of a 4-drug nanosuspension exhibited persistent drug levels in LNMCs, PBMCs, and plasma for 5 weeks. With interspecies scaling and dose adjustment, this 4-in-1 HIV drug-combination could be a long-acting treatment with the potential to target residual virus in tissues and improve patient adherence.
每日口服抗逆转录病毒疗法方案在残留 HIV 持续存在的组织中产生有限的药物暴露，并且存在患者依从性差和药物动力学差异等问题，所有这些都对治疗结果产生负面影响。为了解决这个问题，我们开发了一种组织和细胞靶向的长效 4 合一纳米混悬剂，由洛匹那韦（LPV）、利托那韦、替诺福韦（TFV）和拉米夫定（3TC）组成。在 4 只皮下给药的猕猴中，通过液相色谱-串联质谱法分析了 5 周内血浆、淋巴结单核细胞（LNMCs）和外周血单核细胞（PBMCs）中的药物水平。活性药物（LPV、TFV 和 3TC）的血浆和 PBMC 水平持续 5 周；PBMC 对 LPV、利托那韦和 3TC 的暴露水平分别是血浆中的 12、16 和 42 倍。LPV、TFV 和 3TC 的表观 T 在血浆中分别为 219.1、63.1 和 136.3 h；在 PBMCs 中分别为 1045.7、105.9 和 127.7 h。在第 8 天，LNMCs 中的 LPV、TFV 和 3TC 水平分别是 PBMCs 中的 4.1、5.0 和 1.9 倍，远高于 PBMCs 和血浆中的水平。因此，1 剂 4 药纳米混悬剂在 LNMCs、PBMCs 和血浆中可实现持续 5 周的药物水平。通过种间缩放和剂量调整，这种 4 合一 HIV 药物组合可能成为一种长效治疗方法，具有靶向组织中残留病毒和提高患者依从性的潜力。
