Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection
Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection
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DOI：
10.1016/j.xphs.2018.03.005
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发表时间：
2018-07-01
影响因子：
3.8
通讯作者：
Ho, Rodney J. Y.
中科院分区：
文献类型：
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作者：
McConnachie, Lisa A.;Kinman, Loren M.;Ho, Rodney J. Y.
每日口服抗逆转录病毒治疗方案在残留HIV持续存在的组织中产生有限的药物暴露，并且患者依从性差和药物动力学不同，这些都对结果产生负面影响。为了解决这个问题，我们开发了一种靶向组织和细胞的长效4合1纳米混悬液，由洛匹那韦（LPV）、利托那韦、替诺福韦（TFV）和拉米夫定（3 TC）组成。在皮下给药的4只猕猴中，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（PBMC）中的药物水平。活性药物（LPV、TFV和3 TC）的血浆和PBMC水平持续5周; PBMC暴露于LPV、利托那韦和3 TC的水平分别是血浆中的12、16和42倍。血浆中LPV、TFV和3 TC的表观T-1/2 z分别为219.1、63.1和136.3 h; PBMC中分别为1045.7、105.9和127.7 h。在第8天，LNMCs中的LPV、TFV和3 TC水平分别是PBMC中的4.1倍、5.0倍和1.9倍，并且远高于血浆中的水平。因此，1剂4-药物纳米混悬剂在LNMC、PBMC和血浆中显示出持续5周的药物水平。通过种间缩放和剂量调整，这种4合1 HIV药物组合可能是一种长效治疗，具有靶向组织中残留病毒并提高患者依从性的潜力。(C)2018由Elsevier Inc.出版代表美国药剂师协会
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 chromatographyetandem 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-1/2z 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. (C) 2018 Published by Elsevier Inc. on behalf of the American Pharmacists Association.