Sustained Release of Potent Antiviral Prodrugs for HIV Prevention

摘要 在遏制艾滋病毒流行进展方面取得了重要进展，但新的艾滋病毒感染 这一比例正在超过全球卫生组织设定的目标：2019年，估计有170万人 成为全球新感染艾滋病毒的人。需要新的艾滋病毒暴露前预防(PrEP)战略 迫切需要克服这一令人震惊的预防差距。坚持每日给药方案一直是一个关键 阻碍了以前在易感人群中使用抗逆转录病毒(ARV)药物进行的HIV PrEP临床试验的成功， 未受感染的个体。这一挑战可以通过持续释放或长效抗逆转录病毒药物来缓解 将给药频率降低到每月一次或更长时间的配方，并针对 感染艾滋病毒风险最大的异种人群。一种可注射缓释纳米粒 抗逆转录病毒药物Cabotegravir的配方最近已被美国FDA批准用于HIV PrEP，但这 这项技术有很多缺点：初始浓度很高；颗粒不能 注射后取出应有不良反应；药代动力学(PK)尾部阶段，其中亚 在最后一次注射后，治疗性全身药物浓度可持续一年以上。皮下组织 正在开发使用期限为6个月或更长时间的植入物，用于艾滋病毒PrEP，使用单一试剂； 然而，有效的策略可能需要两种抗逆转录病毒药物。这一生物医学挑战因 缺乏FDA批准的安全、有效、具有足够效力以实现可行植入物的可用试剂 尺寸和使用期为六个月或更长。拟议的努力是在我们以前成功的基础上进行的 在开发缓释药物传递生物医学技术方面取得的成就，并将测试 中心假设是，一种创新的皮下植入系统将提供两种新的有效的ARV制剂 从药物的生物物理化学性质和预期使用期限方面证明初步的可行性。在……里面 目标1，我们将设计、合成和筛选一个基于FDA批准的已建立的新型前药库 来自不同机械阶层的代理人。将使用决策树合理地选择潜在候选人 基于明确定义的量化规则。在目标2中，将为以下目标制定有前途的前药候选方案 使用我们的下一代皮下植入系统持续递送，这些努力将由 在南非进行的用户偏好研究，以微调可修改的设备属性。在《目标3》中，我们将 在小鼠和绵羊身上进行PK和安全性研究，然后在人源化小鼠上进行疗效研究，以确定 如果这些设备可以安全地预防阴道和直肠艾滋病毒感染。该项目建立在已建立的 经验丰富的调查人员的合作，并将促进我们对许多， 系统、持续地提供药物以预防艾滋病毒的相互关联的方面。

ABSTRACT Important progress in curbing the progression of the HIV epidemic has been achieved, but new HIV infection rates are outpacing the targets set by global health organizations: in 2019, an estimated 1.7 million people became newly HIV infected worldwide. New HIV pre-exposure prophylaxis (PrEP) strategies are needed urgently to overcome this alarming prevention gap. Adherence to daily dosing regimens has been a critical impediment to success in previous HIV PrEP clinical trials 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 to intervals of once per month or longer and target the heterogeneous populations most at risk from contracting HIV. An injectable sustained release nanoparticle formulation of the ARV drug cabotegravir recently has been approved by the US FDA for HIV PrEP, but this technology suffers from a number of drawbacks: a high initial concentration burst; the particles cannot be removed following injection should there be an adverse reaction; pharmacokinetic (PK) tail-phase where sub- therapeutic systemic drug concentrations can persist for over 1 year after the last injection. Subdermal implants with a duration of use of six months or longer are being developed for HIV PrEP using a single agent; however, effective strategies likely will require two ARV drugs. This biomedical challenge is exacerbated by the scarcity of safe, efficacious FDA-approved available agents with sufficient potency to enable a feasible implant size and a period of use of six months, or longer. The proposed efforts build on our previous successful accomplishments in developing sustained release drug delivery biomedical technologies and will test the central hypothesis that an innovative subdermal implant system delivering two, new potent ARV agents will demonstrate initial feasibility in terms of drug biophysicochemical properties and expected duration of use. In Aim 1, we will design, synthesize, and screen a library of novel prodrugs based on established, FDA-approved agents from different mechanistic classes. Lead candidates will be selected rationally using a decision tree based on clearly defined, quantitative rules. In Aim 2, promising prodrug candidates will be formulated for sustained delivery using our next-generation subdermal implant system, and these efforts will be guided by user preference research conducted in South Africa to fine-tune modifiable device attributes. In Aim 3, we will conduct PK and safety studies in mice and sheep, followed by efficacy studies in humanized mice to determine if the devices can safely prevent vaginal and rectal HIV infection. The project builds on an established collaboration of highly experienced investigators and will advance our scientific knowledge on the many, interrelated aspects of systemic, sustained drug delivery for HIV prevention.