Systemic Sustained Release Delivery of Antiretroviral Agents for HIV Prevention

抗逆转录病毒药物的全身缓释递送用于预防艾滋病毒

• 批准号: 10327138
• 负责人: Marc Michael Baum
• 金额: $ 78.2万
• 依托单位: OAK CREST INSTITUTE OF SCIENCE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327138
• 关键词: AIDS prevention; Academia; Address; Adherence; Adverse reactions; Anatomy; Animals; Anti-Retroviral Agents; Automobile Driving; Canis familiaris; Characteristics; Chemistry; Clinical; Clinical Trials; Complement; Contracts; Data; Dermal; Development; Devices; Diffusion; Dimensions; Diphosphates; Dose; Drug Controls; Drug Delivery Systems; Drug Exposure; Drug Kinetics; Drug or chemical Tissue Distribution; Effectiveness; Epidemic; Evaluation; Excipients; Feedback; Female; Foreign Bodies; Formulation; Frequencies; Future; Goals; HIV; HIV Infections; HIV-1; Hour; Human; Image; Immune response; Implant; In Vitro; Individual; Industry; Infection; Injectable; Injections; Investigation; Knowledge; Lead; Macaca; Macaca mulatta; Mass Spectrum Analysis; Membrane; Methods; Modeling; Monitor; Mus; Nucleosides; Oral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Population Heterogeneity; Preparation; Prevention; Prevention strategy; Process; Prodrugs; Property; Prophylactic treatment; Proteomics; Public Health; Published Comment; Rattus; Regimen; Research; Reverse Transcriptase Inhibitors; Risk; Safety; Science; Sheep; Site; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Suggestion; Tenofovir; Testing; Ultrasonography; United States National Institutes of Health; Vagina; base; clinical practice; controlled release; design; drug candidate; efficacy study; experience; flexibility; global health; health organization; imaging modality; implant design; implant material; implantation; improved; in vivo; infection rate; innovation; lead candidate; male; manufacturability; meetings; metabolomics; multidisciplinary; next generation; non-invasive imaging; nonhuman primate; particle; penis; pre-clinical; pre-exposure prophylaxis; preclinical development; preclinical study; prevent; prophylactic; prototype; rectal; research clinical testing; response; safety assessment; safety study; simian human immunodeficiency virus; simulation; subcutaneous; success

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.

抽象的 尽管取得了重大进展，但新的艾滋病毒感染率仍远远超过全球卫生组织设定的目标 以遏制疫情的发展。 2017 年，估计有 180 万人新感染艾滋病毒 全球感染。迫切需要新的 HIV 暴露前预防 (PrEP) 策略来克服这一问题 预防差距惊人。坚持每日给药方案已成为推动这一趋势的关键因素 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 可以通过减少剂量的缓释或“长效”抗逆转录病毒制剂来缓解挑战 频率，最好是每月一次或更长的时间间隔，并且最针对异质人群 感染艾滋病毒的风险。几种抗逆转录病毒药物作为注射缓释药物正在进行临床评价 配方，但存在许多缺点：初始浓度突增高；粒子不能 如果出现不良反应，注射后取出；该方法需要特定的抗逆转录病毒药物 理化特性，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) 口服制剂进行 PrEP 替诺福韦 (TFV) 可以预防相当一部分人的 HIV-1 感染。长效 TFV 全身给药制剂将为缓释 PrEP 产品组合添加急需的 NRTI 选项。在之前的 NIH 支持下，我们开发了一种皮下植入物，可提供高效能 前药 TFV 艾拉酚胺 (TAF)。我们评估了原型的药代动力学（PK）和安全性 植入物在小鼠、比格犬和绵羊体内以多种释放速率输送 TAF。这些设备是 在目标剂量窗口内是安全的，使我们能够模拟 HIV-1 PrEP 的人体剂量。拟议的 这些努力建立在这些重要成就的基础上，并将检验一年期 TAF 的中心假设 具有实用物理尺寸的植入物可以安全地预防性 HIV-1 感染。在目标 1 中，我们将设计 下一代 TAF 植入物可利用可扩展技术最大限度地提高药物负载量并控制药物释放 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者。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药物 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) 预防功效研究 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。这 PK-药效关系将在探索性模型中进行研究。该项目将推进我们的 关于缓释系统性 TAF 及其代谢物药理学特性的科学知识 与预防 HIV-1 的口服制剂相比。