Systemic Sustained Release Delivery of Antiretroviral Agents for HIV Prevention

 描述(由申请人提供)：坚持每日给药方案已成为推动在易感、未感染的个人中使用抗逆转录病毒(ARV)药物进行HIV-1暴露前预防(PrEP)临床成功的关键因素。这一挑战可以通过缓释或长效ARV配方来缓解，这些配方可以减少给药频率，理想情况下减少到每月一次或更长时间的间隔。几种抗逆转录病毒药物正在接受临床评估，作为可注射的缓释制剂，但存在一些缺点：初始浓度高；注射后颗粒不能被清除，如果有 不良反应；该方法需要特定的ARV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可以在相当大比例的个人中预防HIV-1感染。用于全身给药的长效TFV配方将为缓释PrEP方案组合增加急需的NRTI。TFV对支持HIV-1复制的目标免疫细胞的生物利用度低，以及该药物的高水溶性，使开发长效制剂极具挑战性。我们的方案克服了这些障碍，使用了一种新的专利皮下植入技术提供的高效前体药物TFV丙氨酰胺(TAF)，该技术提供了线性释放动力学，没有初始爆裂效应。在初步研究中，我们开发了一种TAF植入物的原型，并评估了其在Beagle犬体内40天的药代动力学(PKs)。该植入物保持了该药物活性代谢物TFV二磷酸(TFV-DP)在外周血单个核细胞中的稳定浓度，比推测的HIV-1预防所需浓度高出30倍。拟议的努力建立在这些重要结果的基础上，并将检验核心假设，即具有实际物理尺寸的一年的TAF植入物可以安全地防止性HIV-1感染。在目标1中，我们将在小鼠、狗和猕猴身上设计用于剂量范围研究的TAF植入物。我们将与CMO合作，在项目的五年期限结束时，转让制造技术，以建立在cGMP下制造植入物的能力。在目标2中，我们将评估原型植入物在小鼠、狗和猕猴模型中的PKS和安全性。基质辅助激光解吸成像质谱仪将用于测定TFV和TFV-DP在阴道和直肠组织中的三维分布。总之，这些基础性的科学研究将使我们能够开发出能够根据相应的体外数据预测体内释放率的人类PK模拟模型。在目标3中，将在人源化的小鼠和猕猴中进行HIV-1预防功效研究，以便在探索性模型中研究PK-药效关系。上述活动将是里程碑式的，最终将向美国FDA提交研究新药(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.