Sustained Release of Potent Antiviral Prodrugs for HIV Prevention

持续释放有效的抗病毒前药以预防艾滋病毒

• 批准号: 10617540
• 负责人: Marc Michael Baum
• 金额: $ 72.5万
• 依托单位: OAK CREST INSTITUTE OF SCIENCE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617540
• 关键词: AIDS prevention; Address; Adherence; Adverse reactions; Africa South of the Sahara; African; Amino Acids; Animal Model; Anti-Retroviral Agents; Area; Award; Biological Assay; Biomedical Technology; Clinical Trials; Collaborations; Contracts; Decision Trees; Development; Devices; Dose; Drug Controls; Drug Delivery Systems; Drug Exposure; Drug Kinetics; Drug Screening; Engineering; Epidemic; FDA approved; Female Adolescents; Formulation; Frequencies; Future; Geometry; Goals; HIV; HIV Infections; Health Benefit; Health Personnel; Human; Hydrophobicity; Immune Targeting; Implant; In Vitro; Individual; Infection; Injectable; Injections; Integrase; Kinetics; Knowledge; Lamivudine; Lead; Libraries; Modality; Modeling; Mus; Names; Nucleosides; Oral; Parents; Patients; Penetration; Peptides; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Population Heterogeneity; Predisposition; Prevention; Prevention strategy; Prodrugs; Property; Prophylactic treatment; Public Health; Receptor Cell; Recording of previous events; Rectum; Regimen; Research; Research Personnel; Reverse Transcriptase Inhibitors; Risk; Safety; Science; Sheep; South Africa; System; Tail; Technology; Testing; Therapeutic; Vagina; Viral; aged; chemical synthesis; clinical practice; cytotoxicity; design; drug release kinetics; efficacy study; experience; flexibility; fundamental research; global health; health organization; humanized mouse; hydrophilicity; implant design; improved; in vivo; in vivo evaluation; infection rate; inhibitor; innovation; lead candidate; nanoparticle; next generation; novel; particle; pre-exposure prophylaxis; preclinical safety; preference; prevent; prophylactic; prototype; rectal; response; safety study; scale up; simulation; subcutaneous; success; technology platform; young woman

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.

抽象的 已经取得了抑制HIV流行进展的重要进展，但是新的HIV感染 费率超过了全球卫生组织设定的目标：2019年，估计有170万人 在全球范围内成为新近感染的艾滋病毒。需要新的HIV预防前预防（PREP）策略 紧急克服这一令人震惊的预防差距。遵守日常给药方案是至关重要的 在先前使用抗逆转录病毒（ARV）药物的HIV Prep临床试验中，成功的障碍 未感染的人。可以通过持续释放或长效的ARV来缓解这一挑战 将剂量频率降低到每月一次或更长时间间隔的配方，并针对 艾滋病毒感染艾滋病毒的异质种群最有风险。可注射的持续释放纳米颗粒 最近，美国FDA批准了ARV毒品Cabotegravir的配方 技术遭受了许多缺点：高初始浓度爆发；粒子不能 注射后消除了不良反应。药代动力学（PK）尾相，其中亚 上一次注射后，治疗性全身药物浓度可以持续1年以上。亚层 使用单个药物开发了六个月或更长时间使用六个月或更长时间的植入物； 但是，有效的策略可能需要两种ARV药物。这种生物医学挑战因 安全，有效的FDA批准的可用代理缺乏足够的效力以实现可行的植入物 大小和六个月或更长的使用时间。拟议的努力以我们以前的成功为基础 开发持续释放药物递送生物医学技术的成就，并将测试 中心假设是，创新的下层植入物系统提供了两个新的有效ARV代理 证明了药物生物物理学特性和预期使用持续时间的初始可行性。在 AIM 1，我们将根据已建立的，FDA批准 来自不同机械类别的代理。首席候选人将使用决策树合理选择 基于明确定义的定量规则。在AIM 2中，将为有希望的前药候选人制定 使用我们的下一代亚植入系统进行持续交付，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AIM 3中，我们将 在小鼠和绵羊中进行PK和安全研究，然后在人源化小鼠中进行功效研究以确定 如果设备可以安全防止阴道和直肠HIV感染。该项目建立在既定的 经验丰富的研究人员的合作，并将推进我们对许多人的科学知识 系统性，持续药物递送的相互关联，以预防HIV。