Systemic Sustained Release Delivery of Antiretroviral Agents for HIV Prevention

摘要 尽管取得了重要进展，但新的艾滋病毒感染率远远超过全球卫生组织设定的目标 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。 感染全球。迫切需要新的艾滋病毒暴露前预防（PrEP）策略来克服这一问题 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与抗逆转录病毒（ARV）药物在易感、未感染个体中的临床成功。这 可通过减少剂量的持续释放或“长效”ARV制剂来减轻挑战 频率，理想情况下为每月一次或更长时间的间隔，并针对异质人群， 感染艾滋病毒的风险。几种抗逆转录病毒药物正在进行临床评价，作为注射缓释剂 这些制剂具有许多缺点：高的初始浓度爆发;颗粒不能被 注射后如果有不良反应，应将其移除;该方法需要特定的ARV 这些药物的生理化学特性，极大地限制了候选药物的范围。多个大型临床 试验表明，使用核苷逆转录酶抑制剂（NRTI）的口服制剂的PrEP 替诺福韦（TFV）可以预防相当大比例的个体感染HIV-1。长效TFV 用于全身给药的制剂将在持续释放PrEP的组合中添加急需的NRTI 选项.在先前NIH的支持下，我们开发了一种皮下植入物， 前药TFV阿拉芬胺（TAF）。我们评价了原型药物的药代动力学（PK）和安全性 在小鼠、比格犬和绵羊中以宽范围的释放速率递送TAF的植入物。器械 在目标剂量窗口中是安全的，并允许我们模拟HIV-1 PrEP的人体剂量。 这些努力建立在这些重要成就的基础上，并将检验一个中心假设，即一年的技术援助框架 具有实际物理尺寸植入物可以安全地预防性HIV-1感染。在目标1中，我们设计 下一代TAF植入物使用可扩展的载体来最大化药物负载和控制药物释放， 工艺和可接受的生物医学材料。我们将在大鼠和绵羊中进行PK研究，以帮助选择 在目标2下对绵羊进行广泛安全评估的主要候选人。在这里，植入材料和 将评估赋形剂，以最大限度地提高体内局部耐受性，包括使用创新的靶向 蛋白质组学/代谢组学和非侵入性成像方法。在目标3中，HIV-1（SHIV）预防有效性研究 将使用重复低剂量直肠、阴道和阴茎暴露模型在恒河猴中进行。的 将在探索性模型中研究PK-药效学关系。该项目将推动我们的 关于持续释放全身性TAF及其代谢产物药理学特性的科学知识 在预防HIV-1方面与口服制剂相比。

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.