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: 9204020
• 负责人: Alessandro Grattoni
• 金额: $ 81.99万
• 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/9204020
• 关键词: Address; Adverse effects; Adverse reactions; Animal Model; Anti-Retroviral Agents; Biocompatible; Biological Availability; Clinical; Combined Modality Therapy; Development; Devices; Diffusion; Disease Management; Dose; Drug Delivery Systems; Drug Kinetics; Exhibits; Formulation; Fumarates; Future; Goals; HIV; 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; Prophylactic treatment; Pump; Rattus; Regimen; Research; Research Personnel; Risk; Safety; Serum; Silicon; System; Technology; Tenofovir; Testing; Therapeutic; Translations; United States; Vaccines; Validation; Virus Diseases; Work; World Health Organization; absorption; abstracting; base; compliance behavior; design; dosage; drug efficacy; emtricitabine; experience; high risk; improved; in vivo; innovation; meetings; minimally invasive; mortality; multidisciplinary; nanochannel; nonhuman primate; novel; pre-clinical; prevention service; rectal; research clinical testing; simian human immunodeficiency virus; 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.

抽象的 需要一种能够长期持续释放抗逆转录病毒药物的植入系统来克服 HIV 暴露前预防 (PrEP) 中的患者依从性问题并实现预期的临床结果 该提案的目标是利用经验丰富的团队的丰富经验。 具有多学科背景的研究人员基于令人鼓舞的初步发现，将开发一种 基于纳米技术的新型植入式药物输送装置，纳米通道药物输送系统（nDS）， 用于持续和持续释放抗逆转录病毒药物 该植入物的安全性和有效性，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 这一广泛目标将通过以下具体目标来实现： 目标 1) 开发能够在大鼠和 NHP 中持续持续释放 TAF/FTC 60 天的 nDS 植入物。 两个 nDS 植入物专为小型和大型动物模型设计，并结合了远程控制 失活机制，将与 TAF/FTC 一起开发和测试，以确定体外释放速率。 分析以评估植入物的安全性、测试失活机制并确定药物的药代动力学 nDS 递送的 TAF/FTC 将在健康大鼠模型中进行，目的 2) 评估其药代动力学。 在非人类灵长类动物中，nDS 植入物以目标释放速率持续输送 TAF/FTC 60 天 （NHP）的目标 3）评估通过释放猿猴人类免疫缺陷病毒（SHIV）感染的预防作用。 通过 NHP 直肠挑战从 nDS 植入物中获得 TAF/FTC，随后进行药理学分析。 拟议的工作重点是开发一种新颖的人类临床评估模型。 用于持续递送抗逆转录病毒药物的植入式给药装置及其临床前验证 用于 HIV 感染暴露前预防的药物-设备组合 nDS-TAF/FTC 组合。 有望通过消除问题来提供有关抗逆转录病毒药物在 PrEP 中的疗效的独特信息 与患者依从性、肠道吸收和口服给药的生物利用度有关。 该项目的完成将标志着 nDS 的临床转化迈出重要一步 HIV PrEP 植入物以及针对高感染风险个体的有效预防策略 艾滋病毒感染。