A novel nanochannel system for sustained delivery of Tenofovir Alafenamide Fumarate and Emtricitabine for HIV pre-exposure prophylaxis

一种新型纳米通道系统，用于持续递送富马酸替诺福韦艾拉酚胺和恩曲他滨，用于 HIV 暴露前预防

• 批准号: 9300830
• 负责人: Alessandro Grattoni
• 金额: $ 77.43万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-20 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9300830
• 关键词: Address; Adverse effects; Adverse reactions; Animal Model; Anti-Retroviral Agents; Biological Availability; Clinical; Combined Modality Therapy; Development; Devices; Diffuse; Diffusion; Disease Management; Dose; Drug Delivery Systems; Drug Kinetics; Exhibits; Formulation; Fumarates; Future; Goals; HIV; HIV Infections; HIV-1; Human; Implant; Implantable Infusion Pumps; In Vitro; Individual; Infection prevention; Interruption; Macaca mulatta; Magnetism; Measures; Membrane; Methods; Modeling; Morbidity - disease rate; Nanotechnology; Oral Administration; Outcome; Outpatients; Participant; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pilot Projects; Pre-Clinical Model; Preclinical Testing; Prevention; Prevention strategy; Preventive; Procedures; Pump; Rattus; Regimen; Research; Research Personnel; Risk; Safety; Serum; Silicon; System; Technology; Tenofovir; Testing; Therapeutic; United States; Vaccines; Validation; Virus Diseases; Work; World Health Organization; absorption; base; biomaterial compatibility; clinical translation; compliance behavior; design; dosage; drug efficacy; emtricitabine; experience; high risk; implant design; improved; in vivo; innovation; minimally invasive; mortality; multidisciplinary; nanochannel; nonhuman primate; novel; pre-clinical; pre-exposure prophylaxis; prevention service; rectal; research clinical testing; simian human immunodeficiency virus; subcutaneous; success; truvada

Abstract An implantable system capable of long-term sustained release of antiretroviral drugs is needed to overcome patient adherence issues and achieve desired clinical outcomes in pre-exposure prophylaxis (PrEP) of HIV infection. The goal of this proposal, leveraging the extensive experience from a team of accomplished investigators with multidisciplinary backgrounds and based on encouraging preliminary findings, is to develop a novel, nanotechnology-based, implantable drug delivery device, the nanochannel drug delivery system (nDS), for sustained and constant release of antiretroviral drugs. The safety and efficacy of this implant, used for the delivery of tenofovir alafenamide fumarate and emtricitabine (TAF/FTC), will be validated in vitro and in established animal models. This broad objective will be achieved through the following specific aims: Aim 1) to develop nDS implants capable of sustained and constant release of TAF/FTC in rats and NHP for 60 days. Two nDS implants designed for small and large animal models, and incorporating a remotely controlled deactivation mechanism, will be developed and tested with TAF/FTC to establish release rates in vitro. In vivo analysis to evaluate safety of implant, test the deactivation mechanism, and determine the pharmacokinetics of nDS-delivered TAF/FTC will be conducted in healthy rat models. Aim 2) to assess the pharmacokinetics of constant delivery of TAF/FTC from nDS implants at target release rates for 60 days in non-human primates (NHP). Aim 3) to evaluate prevention of simian-human immunodeficiency virus (SHIV) infection by release of TAF/FTC from nDS implants through rectal challenge in NHP. This will be followed by pharmacometric modeling for future clinical evaluation in humans. The proposed work focuses at developing a novel implantable drug delivery device for the sustained delivery of antiretroviral drugs and the preclinical validation of the drug-device combination for pre-exposure prophylaxis of HIV infection. The nDS-TAF/FTC combination is expected to provide unique information about antiretroviral drugs’ efficacy in PrEP by eliminating issues related to patient compliance, gut absorption, and bioavailability from oral administration. The successful completion of this project will represent a significant step forward toward the clinical translation of the nDS implant for HIV PrEP and an effective preventive strategy for individuals who are at substantial risk of acquiring HIV infection.

摘要 需要一种能够长期持续释放抗逆转录病毒药物的可植入系统来克服 患者依从性问题，并在HIV暴露前预防（PrEP）中实现预期的临床结局 感染该提案的目标是利用一个团队的丰富经验， 具有多学科背景的调查人员，根据令人鼓舞的初步调查结果， 新型的、基于纳米技术的、可植入的药物递送装置，纳米通道药物递送系统（nDS）， 持续不断地释放抗逆转录病毒药物。该植入物用于 富马酸替诺福韦艾拉酚胺和恩曲他滨（TAF/FTC）的递送将在体外和体内进行验证。 建立动物模型。这一广泛目标将通过以下具体目标实现： 开发能够在大鼠和NHP中持续和恒定释放TAF/FTC 60天的nDS植入物。 两种nDS植入物设计用于小型和大型动物模型，并结合了远程控制 失活机制，将开发和测试与TAF/FTC建立体外释放速率。体内 分析，以评价植入物的安全性，测试失活机制，并确定药代动力学 将在健康大鼠模型中进行nDS递送的TAF/FTC。目的2）评价 在非人灵长类动物中以目标释放速率持续60天从nDS植入物中持续递送TAF/FTC （NHP）。目的3）评价释放人免疫缺陷病毒（SHIV）预防猴SHIV感染的效果 通过NHP中的直肠激发，来自nDS植入物的TAF/FTC。随后将进行药物计量学 用于未来人体临床评价的建模。拟议的工作重点是发展一部小说 抗逆转录病毒药物缓释植入装置及其临床前验证 暴露前预防HIV感染的药物-器械组合。nDS-TAF/FTC联合用药 预计将提供关于抗逆转录病毒药物在PrEP中疗效的独特信息， 与患者依从性、肠道吸收和口服给药的生物利用度相关。成功 该项目的完成将标志着向临床翻译NDS迈出了重要的一步 植入艾滋病毒PrEP和有效的预防策略，为个人谁是在获得重大风险 艾滋病毒感染。