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 遏制艾滋病疫情蔓延取得重要进展，但新增艾滋病感染病例 发病率超过了全球卫生组织设定的目标：2019 年估计有 170 万人 成为全球新的艾滋病毒感染者。需要新的 HIV 暴露前预防 (PrEP) 策略 迫切需要克服这一令人震惊的预防差距。坚持每日给药方案至关重要 之前在易感人群中使用抗逆转录病毒 (ARV) 药物开展的 HIV PrEP 临床试验取得成功的障碍 未感染的个体。可以通过缓释或长效抗逆转录病毒药物来缓解这一挑战 将给药频率减少到每月一次或更长时间的制剂，并针对 最容易感染艾滋病毒的异质人群。一种可注射的缓释纳米颗粒 抗逆转录病毒药物 cabotegravir 的配方最近已获得美国 FDA 批准用于 HIV PrEP，但这 该技术存在许多缺点：初始浓度爆发高；粒子不能 如果出现不良反应，注射后取出；药代动力学 (PK) 尾相，其中亚 最后一次注射后，治疗性全身药物浓度可持续 1 年以上。皮下 正在开发使用时间为六个月或更长时间的植入物，用于使用单一药剂的 HIV PrEP； 然而，有效的策略可能需要两种抗逆转录病毒药物。这种生物医学挑战因 缺乏经 FDA 批准且具有足够效力以实现可行植入的安全、有效的可用药物 尺寸和六个月或更长时间的使用期限。拟议的努力建立在我们之前成功的基础上 开发缓释药物递送生物医学技术的成就并将测试 中心假设是，一种创新的皮下植入系统将提供两种新型强效抗逆转录病毒药物 证明药物生物理化特性​​和预期使用持续时间方面的初步可行性。在 目标 1，我们将根据 FDA 批准的既定药物设计、合成和筛选新型前药库 来自不同机械类别的代理。将使用决策树合理选择主要候选人 基于明确定义的定量规则。在目标 2 中，将制定有前途的前药候选物 使用我们的下一代皮下植入系统持续交付，这些努力将由 在南非进行的用户偏好研究，旨在微调可修改的设备属性。在目标 3 中，我们将 在小鼠和绵羊中进行 PK 和安全性研究，然后在人源化小鼠中进行功效研究以确定 如果这些设备可以安全地预防阴道和直肠艾滋病毒感染。该项目建立在既定的 经验丰富的研究人员的合作将提高我们在许多方面的科学知识， 预防艾滋病毒的系统性、持续性药物输送的相互关联的方面。