"NextGen Long-acting Platform: Targeted Combination Antiretrovirals"

靶向长效联合抗逆转录病毒治疗（TLC-ART）计划发现了一种新的 该平台可以将不溶性和可溶性抗逆转录病毒药物一起稳定在纳米混悬液中， 在临床前研究中提供长效（LA）血浆和细胞浓度。先导制剂（称为 TLC-ART 101）结合了三种FDA批准的药物（活性药物成分，API）， 可通用地获得洛匹那韦（LPV）、利托那韦（RTV）和替诺福韦（TFV）。虽然TLC-ART 101可能不是 作为商业产品开发，存在大量临床前数据，并且该程序已收到 FDA的有利监管路径指导。TLC-ART 101比其他TLC-ART领先数年 配方正在开发中。在这项申请中，我们提出了一个首次在人体内，假设驱动，临床试验， 提供关于这种新的下一代LA药物组合平台技术的人体数据。审判将 解决了关于这种新平台的人体药代动力学（PK）和安全性的多个问题。的 项目将由经验丰富的多学科研究领导团队管理。临床试验将 由华盛顿大学艾滋病临床试验单位（一个艾滋病批准的研究地点附属部门）的工作人员进行 与艾滋病临床试验组），由一个独立的数据监测委员会监督，并监测 独立监察员。拟议的试验是一项开放标签、单组研究， 指导剂量和持续时间自适应设计。该试验的假设是，TLC-ART药物组合 纳米颗粒平台是安全的，能够改变三种短效仿制药的PK， 抗逆转录病毒药物，以在人血浆和细胞中产生LA浓度-时间过程。主 临床试验的目的是：1）表征单次给药的血浆浓度-时间过程和PK， 通过皮下注射施用的TLC-ART 101的三种API（LPV、RTV和TFV）的剂量，和2） 表征TLC-ART 101单次皮下注射的安全性和耐受性。该试验还 有4个探索性机制目标，将提供有关细胞靶向特征的信息， TLC-ART 101（意味着细胞内血液和淋巴细胞的API浓度等于或高于 血浆），以及探索3种API的PK参数是否存在性别差异。十二到 16名无HIV的健康受试者将入组4个剂量队列，仔细监测安全性， 使用灵敏的， 根据GLP进行验证试验。来自血液的细胞内API和TFV-二磷酸盐浓度 单核细胞和淋巴结单核细胞（亚组）将与血浆浓度进行比较 以解决平台技术的细胞靶向特性。三年计划包括： 将密切监测里程碑和时间轴，以确保这项创新性临床试验的成功。这些 人类数据将形成利用该平台开发更有效的高活性LA抗病毒组合的基础。

The Targeted Long-acting Combination Antiretroviral Therapy (TLC-ART) Program has discovered a novel platform that can stabilize insoluble and soluble antiretroviral drugs together in a nanosuspension which provides long-acting (LA) plasma and cell concentrations in pre-clinical studies. The lead formulation (called TLC-ART 101) combines three FDA-approved drugs (active pharmaceutical ingredients, APIs) that are available generically lopinavir (LPV), ritonavir (RTV) and tenofovir (TFV). While TLC-ART 101 may not be developed as a commercial product, substantial pre-clinical data exists and the program has received favorable regulatory pathway guidance from the FDA. TLC-ART 101 is years ahead of other TLC-ART formulations in development. In this application, we propose a first-in-human, hypothesis-driven, clinical trial to provide human data about this novel, next generation, LA drug-combination platform technology. The trial will address multiple questions about the human pharmacokinetics (PK) and safety of this new platform. The project will be managed by an experienced, multi-disciplinary Study Leadership Team. The clinical trial will conducted by the staff at the UW AIDS Clinical Trials Unit (a Division of AIDS-approved research site affiliated with the AIDS Clinical Trials Group), overseen by an independent Data Monitoring Committee, and monitored by independent monitors. The proposed trial is an open-label, single-arm study with a pharmacologically- guided dose and duration adaptive design. The trial's hypothesis is that the TLC-ART drug-combination nanoparticle platform is safe and able to transform the PK of three short-acting generic and physically diverse antiretroviral drugs to create a LA concentration-time course in human plasma and cells. The primary objectives of the clinical trial are: 1) To characterize the plasma concentration-time course and PK of a single dose of the three APIs of TLC-ART 101 (LPV, RTV, and TFV) administered by sub-cutaneous injection, and 2) To characterize the safety and tolerability of a single subcutaneous injection of TLC-ART 101. The trial also has 4 exploratory mechanistic objectives that will provide information about the cell-targeting characteristics of TLC-ART 101 (meaning intracellular blood and lymphoid cells have equal or higher API concentrations than plasma), as well as exploring whether there are sex differences in the PK parameters of the 3 APIs. Twelve to 16 healthy persons without HIV will be enrolled in dose cohorts of 4, monitored carefully for safety, and undergo intensive PK sampling (18 timepoints over 35 days) for plasma API concentrations using a sensitive, validated assay done under GLP. Intracellular API and TFV-diphosphate concentrations from blood mononuclear cells and lymph node mononuclear cells (in a subset) will be compared to plasma concentrations to address the cell-targeting characteristics of the platform technology. The 3-year proposal includes major milestones and a timeline that will be closely monitored to ensure success of this innovative clinical trial. These human data will form a basis to develop more potent highly active LA antiviral combinations with this platform.