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Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation.
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2018-02-10 , DOI: 10.1016/j.jconrel.2018.02.003
John C Kraft 1 , Lisa A McConnachie 1 , Josefin Koehn 1 , Loren Kinman 1 , Jianguo Sun 1 , Ann C Collier 2 , Carol Collins 1 , Danny D Shen 1 , Rodney J Y Ho 3
Affiliation  

Existing oral antiretroviral (ARV) agents have been shown in human studies to exhibit limited lymph node penetration and lymphatic drug insufficiency. As lymph nodes are a reservoir of HIV, it is critical to deliver and sustain effective levels of ARV combinations in these tissues. To overcome lymph node drug insufficiency of oral combination ARV therapy (cART), we developed and reported a long-acting and lymphocyte-targeting injectable that contains three ARVs-hydrophobic lopinavir (LPV) and ritonavir (RTV), and hydrophilic tenofovir (TFV)-stabilized by lipid excipients in a nanosuspension. A single subcutaneous (SC) injection of this first-generation formulation of drug combination nanoparticles (DcNPs), named TLC-ART101, provided persistent ARV levels in macaque lymph node mononuclear cells (LNMCs) for at least 1 week, and in peripheral blood mononuclear cells (PBMCs) and plasma for at least 2 weeks, demonstrating long-acting pharmacokinetics for all three drugs. In addition, the lymphocyte-targeting properties of this formulation were demonstrated by the consistently higher intracellular drug concentrations in LNMCs and PBMCs versus those in plasma. To provide insights into the complex mechanisms of absorption and disposition of TLC-ART101, we constructed novel mechanism-based pharmacokinetic (MBPK) models. Based upon plasma PK data obtained after single administration of TLC-ART101 (DcNPs) and a solution formulation of free triple-ARVs, the models feature uptake from the SC injection site that respectively routes free and nanoparticle-associated ARVs via the blood vasculature and lymphatics, and their eventual distribution into and clearance from the systemic circulation. The models provided simultaneous description of the complex long-acting plasma and lymphatic PK profiles for all three ARVs in TLC-ART101. The long-acting PK characteristics of the three drugs in TLC-ART101 were likely due to a combination of mechanisms including: (1) DcNPs undergoing preferential lymphatic uptake from the subcutaneous space, (2) retention in nodes during lymphatic first-pass, (3) subsequent slow release of ARVs into blood circulation, and (4) limited extravasation of DcNP-associated ARVs that resulted in longer persistence in the circulation.

中文翻译:

基于机制的药代动力学(MBPK)模型描述了由长效抗HIV药物组合纳米颗粒制剂提供的三种抗逆转录病毒药的复杂血浆动力学。

在人体研究中,现有的口服抗逆转录病毒药物(ARV)已显示出有限的淋巴结渗透和淋巴管供血不足。由于淋巴结是HIV的储存库,因此在这些组织中递送和维持有效水平的ARV组合至关重要。为了克服口服联合抗逆转录病毒疗法(cART)的淋巴结药物不足,我们开发并报道了一种长效和靶向淋巴细胞的注射剂,其中包含三种抗逆转录病毒药物:疏水性洛匹那韦(LPV)和利托那韦(RTV),以及亲水性替诺福韦(TFV) -在纳米悬浮液中被脂质赋形剂稳定。对该药物组合纳米颗粒(DcNPs)的第一代制剂进行一次皮下(SC)注射,命名为TLC-ART101,在猕猴淋巴结单核细胞(LNMCs)中提供了至少1周的持续抗逆转录病毒水平,以及在外周血单核细胞(PBMC)和血浆中至少持续2周,证明了这三种药物的长效药代动力学。此外,该制剂的淋巴细胞靶向特性通过LNMCs和PBMCs中始终高于血浆中的细胞内药物浓度来证明。为了提供对TLC-ART101吸收和处置的复杂机制的见解,我们构建了基于新型机制的药代动力学(MBPK)模型。基于单次施用TLC-ART101(DcNPs)后获得的血浆PK数据和游离三重ARV的溶液制剂,这些模型的特征在于从SC注射部位摄取,分别通过血管和淋巴管传导游离的和纳米颗粒相关的ARV。 ,以及它们最终分布于系统性循环中以及从系统性循环中清除。该模型同时提供了TLC-ART101中所有三个ARV的复杂长效血浆和淋巴PK曲线的描述。这三种药物在TLC-ART101中的长效PK特性可能是由于多种机制共同导致的,这些机制包括:(1)DcNPs从皮下空间进行优先淋巴摄取,(2)淋巴初次通过时保留在淋巴结中,( 3)随后将ARV缓慢释放到血液循环中,以及(4)限制了DcNP相关的ARV的外渗,从而延长了血液中的持久性。
更新日期:2018-02-10
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