Systemic Sustained Release Delivery of Antiretroviral Agents for HIV Prevention

用于预防艾滋病毒的抗逆转录病毒药物的全身缓释递送

基本信息

批准号：
10654774
负责人：
Marc Michael Baum
金额：
$ 76.6万
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/10654774
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 Membrane Methods Modeling Monitor Mus Nucleosides Oral Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Pharmacodynamics Pharmacology Population Heterogeneity Porosity Predisposition Preparation Prevention Prevention strategy Process Prodrugs Property Prophylactic treatment Proteomics Public Health Published Comment Rattus Rectum Regimen Research Reverse Transcriptase Inhibitors Risk Safety Science Sheep Site Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Tenofovir Testing Ultrasonography United States National Institutes of Health Vagina Writing 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 mass spectrometric imaging meetings metabolomics multidisciplinary next generation non-invasive imaging nonhuman primate particle penis pharmacologic pre-Investigational New Drug meeting 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 2017 年，估计有 180 万人新感染艾滋病毒。迫切需要新的艾滋病毒暴露前预防（PrEP）策略来克服这一问题。惊人的预防差距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。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几种抗逆转录病毒药物作为注射缓释药物正在接受临床评估。配方，但存在许多缺点：颗粒的初始浓度较高，不能爆发；如果出现不良反应，则在注射后移除；该方法需要特定的抗逆转录病毒药物理化特性，极大地限制了多个候选药物的大规模临床。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 感染一种长效 TFV。全身给药制剂将为缓释 PrEP 产品组合添加急需的 NRTI 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。我们评估了原型药物 TFV 艾拉酚胺 (TAF) 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不同的释放率输送 TAF。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。以这些重要成就和努力为基础，将检验一年期 TAF 的中心假设在目标 1 中，我们将设计具有实用物理尺寸的植入物，可以安全地预防性 HIV-1 感染。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目标 3 中的蛋白质组学/代谢组学和非侵入性成像方法，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。该项目将在探索性模型中研究 PK 药效关系。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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fundamental aspects of long-acting tenofovir alafenamide delivery from subdermal implants for HIV prophylaxis.

从皮下植入物递送长效替诺福韦艾拉酚胺以预防艾滋病毒的基本方面。

DOI：
发表时间：
2022-05-17
期刊：
影响因子：
4.6
作者：
Gunawardana, Manjula;Remedios;Sanchez, Debbie;Webster, Simon;Castonguay, Amalia E;Webster, Paul;Buser, Christopher;Moss, John A;Trinh, MyMy;Beliveau, Martin;Hendrix, Craig W;Marzinke, Mark A;Tuck, Michael;Caprioli, Richard M;Re
通讯作者：
Re

Preclinical Considerations for Long-acting Delivery of Tenofovir Alafenamide from Subdermal Implants for HIV Pre-exposure Prophylaxis.

用于 HIV 暴露前预防的皮下植入物长效递送替诺福韦艾拉酚胺的临床前考虑因素。

DOI：
发表时间：
2023-07
期刊：
影响因子：
3.7
作者：
Gunawardana, Manjula;Remedios;Sanchez, Debbie;Fanter, Rob;Webster, Simon;Webster, Paul;Moss, John A;Trinh, MyMy;Beliveau, Martin;Ramirez, Christina M;Marzinke, Mark A;Kuo, Joseph;Gallay, Philippe A;Baum, Marc M
通讯作者：
Baum, Marc M

Acute antagonism in three-drug combinations for vaginal HIV prevention in humanized mice.

三种药物组合对人源化小鼠阴道艾滋病毒预防的急性拮抗作用。