Systemic Sustained Release Delivery of Antiretroviral Agents for HIV Prevention

 描述（由申请方提供）：坚持每日给药方案已成为驱动抗逆转录病毒（ARV）药物在易感、未感染个体中进行HIV-1暴露前预防（PrEP）临床成功的关键因素。这种挑战可以通过减少给药频率的持续释放或“长效”ARV制剂来缓解，理想情况下，间隔为每月一次或更长时间。几种抗逆转录病毒药物正在作为可注射持续释放制剂进行临床评价，但存在许多缺点：高初始浓度爆发;如果存在药物释放，则在注射后不能除去颗粒。 不良反应;该方法需要特定的抗逆转录病毒药物的理化特性，极大地限制了候选药物的范围。最近的四项大规模临床试验表明，使用核苷逆转录酶抑制剂（NRTI）替诺福韦（TFV）制剂的PrEP可以预防相当大比例的个体感染HIV-1。用于全身给药的长效TFV制剂将为持续释放PrEP选项组合添加急需的NRTI。TFV对支持HIV-1复制的靶向免疫细胞的低生物利用度和药物的高水溶性使得开发长效制剂极具挑战性。我们的建议克服了这些障碍，通过使用高效的前药TFV阿拉芬胺（TAF），从一个新的，专利，皮下植入技术，提供线性释放动力学，没有初始爆发效应。在初步研究中，我们开发了一种原型TAF植入物，并在比格犬中评价了其40天的药代动力学（PK）。该植入物在外周血单核细胞中维持TFV二磷酸盐（TFV-DP）（药物的活性代谢产物）的稳态浓度，该浓度比假定的HIV-1预防所需的浓度高30倍。拟议的努力建立在这些重要结果的基础上，并将测试核心假设，即具有实用物理尺寸的一年期TAF植入物可以安全地预防性HIV-1感染。在目标1中，我们将设计TAF植入物用于小鼠、犬和猕猴的剂量范围研究。我们将与CMO合作，转让制造技术，以便在该项目的五年期结束时建立在cGMP下制造植入物的能力。在目标2中，我们将评价原型植入物在小鼠、犬和猕猴模型中的PK和安全性。将使用基质辅助激光解吸成像质谱法测定阴道和直肠组织中TFV和TFV-DP的3D分布。总之，这些基础科学研究将使我们能够开发人类PK模拟模型，从而能够根据相应的体外数据预测体内释放速率。在目标3中，将在人源化小鼠和猕猴中进行HIV-1预防有效性研究，以便在探索性模型中研究PK-药效学关系。上述活动将是里程碑式的，最终将向美国FDA提交研究性新药（IND）申请，使该技术在项目成功完成后迅速进入临床试验。

 DESCRIPTION (provided by applicant): Adherence to daily dosing regimens has emerged as a critical factor driving the clinical success of HIV-1 pre- exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs in susceptible, uninfected individuals. This challenge can be mitigated with sustained release or "long-acting" ARV formulations that reduce dosing frequency, ideally to intervals of once per month or longer. Several ARV drugs are undergoing clinical evaluation as injectable sustained release formulations, but suffer from a number of drawbacks: a high initial concentration burst; the particles cannot be removed following injection should there be an adverse reaction; the approach requires specific ARV physiochemical characteristics, dramatically limiting the range of candidate drugs. Four recent large-scale clinical trials have shown that PrEP using preparations of the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir (TFV) can prevent HIV-1 infection in a significant proportion of individuals. A long-acting TFV formulation for systemic dosing would add a much-needed NRTI to the portfolio of sustained release PrEP options. The low bioavailability of TFV to target immune cells supporting HIV-1 replication and the drug's high aqueous solubility make developing a long-acting formulation extremely challenging. Our proposal overcomes these hurdles by using the highly potent prodrug TFV alafenamide (TAF) delivered from a novel, patented, subcutaneous implant technology that provides linear release kinetics with no initial burst effect. In preliminary studis, we have developed a prototype TAF implant and evaluated its pharmacokinetics (PKs) in beagle dogs over 40 days. The implant maintained steady-state concentrations of TFV diphosphate (TFV-DP), the drug's active metabolite, in peripheral blood mononuclear cells that were thirty times higher than required for putative HIV-1 prophylaxis. The proposed efforts build on these important results and will test the central hypothesis that a one-year TAF implant with practical physical dimensions can safely prevent sexual HIV-1 infection. In Aim 1, we will design TAF implants for dose-ranging studies in mice, dogs, and macaques. We will work with a CMO to transfer the fabrication technology to build the capacity for manufacturing the implants under cGMP at the end of the project's five-year term. In Aim 2, we will evaluate the PKs and safety of the prototype implants in mouse, dog, and macaque models. Matrix-assisted laser desorption imaging mass spectrometry will be used to determine the 3D distribution of TFV and TFV-DP in vaginal and rectal tissues. Together, these foundational scientific studies will allow us to develo human PK simulation models that enable prediction of in vivo release rates from corresponding in vitro data. In Aim 3, HIV-1 prevention efficacy studies will be carried out in humanized mice and macaques, allowing the PK-pharmacodynamic relationships to be investigated in exploratory models. The above activities will be milestone-driven, culminating with submission of an Investigational New Drug (IND) application to the US FDA, allowing the technology to rapidly advance into clinical trials following the project's successful completion.