Ultra-long Acting Transcutaneously Refillable Islatravir Nanofluidic Implant for HIV Pre-Exposure

用于 HIV 暴露前的超长效经皮可再填充 Islatravir 纳米流体植入物

• 批准号: 10481727
• 负责人: Alessandro Grattoni
• 金额: $ 80.81万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481727
• 关键词: AIDS prevention; Address; Adherence; Anti-Retroviral Agents; Chronic; Clinical; Clinical Research; Complex; Developing Countries; Development; Devices; Diffuse; Diffusion; Dose; Drug Controls; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Equipment; Excision; Fatigue; Formulation; Goals; HIV; HIV Infections; HIV antiretroviral; Heterogeneity; Human; Implant; Implantable Infusion Pumps; In Vitro; Individual; Injectable; Intravenous; Kinetics; Legal patent; Logistics; Manuals; Medical; Membrane; Modeling; Nickel; Operative Surgical Procedures; Oral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Physiological; Polymers; Prevention; Prevention strategy; Preventive; Pump; Recording of previous events; Regimen; Research; Route; Safety; Scanning Electron Microscopy; Silicon; Solid; Syringes; System; Technology; Testing; Therapeutic; Tissues; Vagina; Virus Diseases; base; biomaterial compatibility; clinical development; clinical translation; effectiveness evaluation; experience; global health; high risk; implantation; improved; innovation; minimally invasive; multidisciplinary; nanochannel; nanofluidic; nonhuman primate; penis; pill; pre-clinical; pre-exposure prophylaxis; preference; prevent; prophylactic; public health relevance; rectal; response; side effect; silicon carbide; simian human immunodeficiency virus; subcutaneous; transmission process; treatment duration; tripolyphosphate; viral transmission

Abstract Long-acting (LA) pre-exposure prophylactic (PrEP) strategies offer the promise of improving adherence to therapeutic regimen for maximal HIV preventive efficacy. Key attributes of zero-order release kinetics, long-term drug delivery, user-independent dosing, therapeutic discretion, safety for chronic use and retrievability are desirable criteria for successful widespread clinical PrEP implementation. To date, LA PrEP strategies do not sufficiently address the aforementioned criteria. Our goal is to address these limitations by developing an ultra- long acting islatravir (ISL) delivery implant with an unprecedented release duration of at least 2 years uninterrupted for durable and safe HIV prevention independent of user adherence. To achieve this goal, we propose the NanoDDI, a transcutaneously refillable subcutaneous nanofluidic drug delivery implant for sustained and constant ISL release. The NanoDDI comprises a newly patented nanofluidic membrane, and ports for rapid, minimally invasive transcutaneous drug refilling. Refilling is performed manually via a syringe without any complex pumps or equipment to extend implant use duration beyond 2 years. The nanofluidic membrane use nanochannels to control drug release through passive diffusion without pumping mechanisms, permitting discrete, long-term user-independent dosing. Unlike injectables or other LA polymeric strategies, NanoDDI avoids burst and decay release. Zero-order release kinetics is achieved independent of physiological conditions, regardless of interindividual heterogeneity. Importantly, the NanoDDI addresses user preferences for discretion and longer dose duration. Here we will test the hypothesis that constant and sustained ISL delivery from NanoDDI will achieve preventative drug levels for a 2-year duration and effectively prevent SHIV infection in non-human primates (NHP). This proposal outlines a comprehensive preclinical framework fundamental for developing NanoDDI as a HIV PrEP platform, leveraging the team’s experience in pre-clinical and clinical HIV PrEP, long-acting drug delivery, drug formulation, and antiretroviral pharmacology. We aim 1) to develop and optimize NanoDDI and ISL formulation for sustained and constant release; 2) to assess pharmacokinetics (PK), tolerability, and safety of NanoDDI-ISL for 2 years in NHP and evaluate effectiveness of transcutaneous drug refilling; and 3) to comprehensively evaluate PrEP efficacy of NanoDDI-ISL in NHPs using 4 routes of simian HIV transmission, namely rectal, penile, vaginal and intravenous. Our multidisciplinary team has a solid history of collaborative HIV PrEP studies with long-acting drug delivery implants and will receive Merck’s scientific and technical support and drug supply for this study. We will use a milestone-driven research approach to advance the NanoDDI-ISL technology towards the ultimate goal of clinical translation.

摘要 长效（LA）暴露前预防（PrEP）策略提供了改善依从性的承诺， 最大限度地预防艾滋病毒的治疗方案。零级释放动力学的关键属性，长期 药物递送、用户独立给药、治疗自由裁量权、长期使用的安全性和可回收性是 成功广泛实施PrEP临床的理想标准。到目前为止，LA PrEP策略不 充分体现上述标准。我们的目标是通过开发一种超 长效islatravir（ISL）递送植入物，具有前所未有的至少2年的释放持续时间 不间断地进行持久和安全的艾滋病毒预防，而不依赖于用户的依从性。为了实现这一目标，我们 提出NanoDDI，一种经皮可再填充的皮下纳米流体药物递送植入物，用于持续 和不断的ISL释放。NanoDDI包括一个新专利的纳米流体膜，和端口的快速， 微创经皮药物再填充。重新填充通过注射器手动进行，无需任何 复杂的泵或设备，以延长植入物使用时间超过2年。纳米流体膜的用途 纳米通道通过被动扩散控制药物释放，而无需泵送机制， 离散的、长期的用户独立给药。与注射剂或其他LA聚合物策略不同，NanoDDI 避免爆裂和衰变释放。零级释放动力学不依赖于生理条件， 而不考虑个体间的异质性。重要的是，NanoDDI解决了用户的自由裁量权偏好 和更长的给药持续时间。 在此，我们将检验NanoDDI的恒定和持续ISL递送将实现预防性 维持2年的药物水平，并有效预防非人灵长类动物（NHP）的SHIV感染。这 一项提案概述了将NanoDDI开发为HIV PrEP的全面临床前框架 平台，利用团队在临床前和临床HIV PrEP，长效药物输送，药物治疗， 制剂和抗逆转录病毒药理学。我们的目标是1）开发和优化NanoDDI和ISL配方 用于缓释和恒定释放; 2）评估NanoDDI-ISL的药代动力学（PK）、耐受性和安全性 在NHP中进行2年，并评估经皮药物再填充的有效性;以及3）全面 评价NanoDDI-ISL在NHP中的PrEP有效性，使用4种猴HIV传播途径，即直肠，阴茎， 阴道和静脉注射。 我们的多学科团队在长效药物输送的HIV PrEP合作研究方面有着坚实的历史 植入物，并将获得默克的科学和技术支持以及本研究的药物供应。我们将使用一个 里程碑驱动的研究方法，以推进NanoDDI-ISL技术实现临床的最终目标 翻译.