Systemic Sustained Release Delivery of Antiretroviral Agents for HIV Prevention

摘要 新的艾滋病毒感染率远远超过全球卫生组织设定的目标，尽管取得了重大进展 在遏制疫情发展方面的作用。2017年，估计有180万人成为新的艾滋病毒感染者 在全球范围内感染。迫切需要新的艾滋病毒暴露前预防(PrEP)战略来克服这一点 令人震惊的预防差距。坚持每日给药方案已成为推动 HIV-1 PrEP联合抗逆转录病毒(ARV)药物在易感、未感染患者中的临床成功。这 挑战可以通过缓释或减少剂量的长效ARV制剂来缓解 频率，最好是每月一次或更长时间的间隔，目标是最不同类型的人群 感染艾滋病毒的风险。几种抗逆转录病毒药物正在接受临床评估，作为可注射缓释药物 配方，但有一些缺点：高初始浓度突发；颗粒不能 如果出现不良反应，注射后取下；该方法需要特定的抗逆转录病毒药物 物理化学特性，极大地限制了候选药物的范围。多家大型临床医院 试验表明，PrEP使用口服制剂的核苷逆转录酶抑制剂(NRTI) 替诺福韦(TFV)可以在相当大比例的个人中预防艾滋病毒-1感染。长效TFV 全身给药的配方将为缓释PrEP产品组合增加急需的NRTI 选择。在之前NIH的支持下，我们已经开发出一种皮下植入物，可以提供高度有效的 前药TFV丙氨酰胺(TAF)。我们评价了样机的药代动力学和安全性。 在小鼠、比格犬和绵羊体内广泛释放TAF的植入物。这些设备是 在目标剂量窗口中是安全的，并允许我们模拟HIV-1PrEP的人体剂量。建议数 这些努力建立在这些重要成就的基础上，并将检验以下中心假设：一年的TAF 具有实用物理尺寸的植入物可以安全地防止性HIV-1感染。在目标1中，我们将设计 新一代TAF植入物使用可扩展的技术最大限度地提高载药量和控制药物释放 工艺和可接受的生物医学材料。我们将在老鼠和绵羊身上进行PK研究，以帮助选择 在目标2下，在绵羊身上进行广泛的安全性评估的主要候选者。 将对赋形剂进行评估，以最大限度地提高体内局部耐受性，包括使用创新的靶向 蛋白质组/代谢组学和非侵入性成像方法。在目标3中，艾滋病毒-1(SIV)预防效果研究 将使用重复的低剂量直肠、阴道和阴茎暴露模型在恒河猴身上进行。这个 PK-药效学关系将在探索性模型中进行研究。该项目将推进我们的 缓释全身性TAF及其代谢物药理性质的科学认识 在预防艾滋病毒-1方面与口服配方进行比较。

ABSTRACT New HIV infection rates far outpace the targets set by global health organizations, despite important progress in curbing the progression of the epidemic. In 2017, an estimated 1.8 million people became newly HIV infected globally. New HIV pre-exposure prophylaxis (PrEP) strategies are needed urgently to overcome this alarming prevention gap. Adherence to daily dosing regimens has emerged as a critical factor driving the clinical success of HIV-1 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, and target the heterogeneous populations most at risk from contracting HIV. 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. Multiple large-scale clinical trials have shown that PrEP using oral 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. Under previous NIH support we have developed a subdermal implant delivering the highly potent prodrug TFV alafenamide (TAF). We have evaluated the pharmacokinetics (PKs) and safety of prototype implants delivering TAF over a wide range of release rates in mice, beagle dogs, and sheep. The devices were safe in the target dosing window and allowed us to simulate a human dose for HIV-1 PrEP. The proposed efforts build on these important accomplishments 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 the next generation TAF implant to maximize drug loading and control of drug release using scalable processes and acceptable biomedical materials. We will conduct PK studies in rats and sheep to help select lead candidates for extensive safety assessment in sheep under Aim 2. Here, the implant materials and excipients will be evaluated to maximize local tolerance in vivo, including using innovative targeted proteomic/metabolomic and non-invasive imaging methods. In Aim 3, HIV-1 (SHIV) prevention efficacy studies will be carried out in rhesus macaques using repeat low dose rectal, vaginal, and penile exposure models. The PK-pharmacodynamic relationships will be investigated in exploratory models. The project will advance our scientific knowledge on the pharmacologic properties of sustained release systemic TAF and its metabolites compared with oral formulations in the context of HIV-1 prevention.