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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的新的艾滋病毒感染率远远超过全球卫生组织设定的目标，目的地的重要进展在遏制流行病的进展中。 2017年，估计有180万人成为新的艾滋病毒全球感染。迫切需要采取新的HIV暴露前预防（PREP）策略来克服这一点令人震惊的预防差距。遵守日常给药方案已成为推动该驱动的关键因素在易感性的未感染个体中使用抗逆转录病毒（ARV）药物进行HIV-1 PREP的临床成功。这可以通过持续释放或“长效” ARV公式来缓解挑战，以减少给药频率，理想情况，每月一次或更长时间间隔一次，并且最多针对异质种群患艾滋病毒的风险。几种ARV药物正在接受临床评估，作为可注射的持续释放公式，但遭受了许多缺点：高初始浓度爆发；粒子不能注射后消除了不良反应。该方法需要特定的ARV 理化特征，极大地限制了候选药物的范围。多个大规模临床试验表明，使用核侧逆转录酶抑制剂（NRTI）的口服制剂进行准备 Tenofovir（TFV）可以防止大部分个体中的HIV-1感染。长效TFV 全身剂量的公式将为持续发布准备的投资组合增加急需的NRTI 选项。在先前的NIH支持下，我们已经开发了一个下属植入物，提供了高度有效的前药TFV Alafenamide（TAF）。我们已经评估了原型的药代动力学（PK）和安全性植入物在小鼠，小猎犬和绵羊的众多释放率上输送TAF。设备是在目标给药窗口中安全，并允许我们模拟人剂量的HIV-1准备。提议努力以这些重要的成就为基础，并将检验一个为期一年的TAF的中心假设具有实际物理维度的植入物可以安全防止性HIV-1感染。在AIM 1中，我们将设计下一代TAF植入物可使用可伸缩的药物释放和控制药物释放过程和可接受的生物医学材料。我们将在老鼠和绵羊上进行PK研究，以帮助选择在AIM 2下的绵羊中广泛的安全评估的首席候选人。在这里，植入物材料和将评估赋形剂以最大化体内局部耐受性，包括使用以创新的针对性蛋白质组学/代谢组和非侵入性成像方法。在AIM 3中，HIV-1（SHIV）预防效率研究将使用重复的低剂量直肠，阴道和阴茎暴露模型在恒河猕猴中进行。 PK-Pharmacodynalnic关系将在探索模型中进行研究。该项目将推动我们的关于持续释放的系统性TAF及其代谢物的药物特性的科学知识与HIV-1预防背景下的口服公式相比。