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：
9277368
负责人：
Marc Michael Baum
金额：
$ 83.52万
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：
2015
资助国家：
美国
起止时间：
2015-06-26 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9277368
关键词：
AIDS prevention Academia Address Adherence Adverse reactions Anti-Retroviral Agents Automobile Driving Biological Assay Biological Availability Canis familiaris Cells Characteristics Chemistry Clinical Clinical Research Clinical Trials Complement Cyclic GMP Data Devices Dimensions Diphosphates Dose Drug Delivery Systems Drug Exposure Drug Kinetics Drug or chemical Tissue Distribution Formulation Foundations Frequencies Goals HIV HIV-1 Half-Life Human Hybrids Image Immune Immune Targeting Implant In Vitro Individual Industry Infection Injectable Injection of therapeutic agent Integrase Inhibitors Investigation Investigational New Drug Application Kinetics Knowledge Laboratories Lasers Legal patent Liquid substance Macaca Macaca nemestrina Mass Spectrum Analysis Measurement Methods Modeling Molds Mus Nucleosides Oral Outcome Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacodynamics Pharmacology Polyvinyl Alcohol Preparation Prevention Prevention strategy Prodrugs Property Prophylactic treatment Public Health Regimen Reporting Research Reverse Transcriptase Inhibitors Safety Science Silicones Solubility Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Supporting Cell Technology Technology Transfer Tenofovir Testing Time Tissues Toxic effect Vagina Work aqueous base biocompatible polymer clinical practice design drug candidate efficacy study experience flexibility humanized mouse implant design improved in vivo manufacturing process meetings models and simulation nanoformulation nanoparticle non-nucleoside reverse transcriptase inhibitors novel particle pharmacodynamic model pre-exposure prophylaxis preclinical development predictive modeling prevent prototype public health relevance rectal research clinical testing response subcutaneous success

项目摘要

DESCRIPTION (provided by applicant): Adherence to daily dosing regimens has emerged as a critical factor driving the clinical success of HIV-1 pre- exposure prophylaxis (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. 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. Four recent large-scale clinical trials have shown that PrEP using 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. The low bioavailability of TFV to target immune cells supporting HIV-1 replication and the drug's high aqueous solubility make developing a long-acting formulation extremely challenging. Our proposal overcomes these hurdles by using the highly potent prodrug TFV alafenamide (TAF) delivered from a novel, patented, subcutaneous implant technology that provides linear release kinetics with no initial burst effect. In preliminary studis, we have developed a prototype TAF implant and evaluated its pharmacokinetics (PKs) in beagle dogs over 40 days. The implant maintained steady-state concentrations of TFV diphosphate (TFV-DP), the drug's active metabolite, in peripheral blood mononuclear cells that were thirty times higher than required for putative HIV-1 prophylaxis. The proposed efforts build on these important results 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 TAF implants for dose-ranging studies in mice, dogs, and macaques. We will work with a CMO to transfer the fabrication technology to build the capacity for manufacturing the implants under cGMP at the end of the project's five-year term. In Aim 2, we will evaluate the PKs and safety of the prototype implants in mouse, dog, and macaque models. Matrix-assisted laser desorption imaging mass spectrometry will be used to determine the 3D distribution of TFV and TFV-DP in vaginal and rectal tissues. Together, these foundational scientific studies will allow us to develo human PK simulation models that enable prediction of in vivo release rates from corresponding in vitro data. In Aim 3, HIV-1 prevention efficacy studies will be carried out in humanized mice and macaques, allowing the PK-pharmacodynamic relationships to be investigated in exploratory models. The above activities will be milestone-driven, culminating with submission of an Investigational New Drug (IND) application to the US FDA, allowing the technology to rapidly advance into clinical trials following the project's successful completion.

描述（由申请人提供）：坚持每日给药方案已成为推动抗逆转录病毒（ARV）药物在易感、未感染个体中进行 HIV-1 暴露前预防（PrEP）临床成功的关键因素。这一挑战可以得到缓解。缓释或“长效”抗逆转录病毒制剂可减少给药频率，最好是每月一次或更长时间的间隔，几种抗逆转录病毒药物正在进行临床评估。注射缓释制剂，但存在许多缺点：初始浓度较高，注射后颗粒无法去除；不良反应；该方法需要特定的 ARV 理化特性，极大地限制了候选药物的范围。最近的四项大规模临床试验表明，使用核苷逆转录酶抑制剂 (NRTI) 替诺福韦 (TFV) 制剂可以预防 HIV-1。用于全身给药的长效 TFV 制剂将为缓释 PrEP 方案组合添加急需的 NRTI TFV 的低生物利用度。支持 HIV-1 复制的免疫细胞和该药物的高水溶性使得开发长效制剂极具挑战性，我们的建议通过使用新型专利皮下植入技术提供的高效前药 TFV 艾拉酚胺 (TAF) 克服了这些障碍。在初步研究中，我们开发了一种 TAF 植入物原型，并在比格犬中评估了该植入物在 40 天内的药代动力学 (PK)。外周血单核细胞中药物的活性代谢物 TFV 二磷酸 (TFV-DP) 的稳态浓度比假定的 HIV-1 预防所需的浓度高出 30 倍。拟议的努力建立在这些重要结果的基础上，并将测试主要结果。假设具有实用物理尺寸的一年 TAF 植入物可以安全地预防性 HIV-1 感染。在目标 1 中，我们将设计用于小鼠、狗和猕猴的剂量范围研究的 TAF 植入物。与 CMO 合作，转让制造技术，以在项目五年期结束时建立根据 cGMP 制造植入物的能力。在目标 2 中，我们将评估原型植入物在小鼠、狗、小鼠体内的 PK 和安全性。基质辅助激光解吸成像质谱法将用于确定 TFV 和 TFV-DP 在阴道和直肠组织中的 3D 分布，这些基础科学研究将使我们能够开发人类 PK 模拟模型，能够根据相应的体外数据预测体内释放率。在目标 3 中，将在人源化小鼠和猕猴中进行 HIV-1 预防功效研究，从而可以探索性地研究 PK 药效关系。上述活动将是里程碑式的，最终将向美国 FDA 提交研究性新药 (IND) 申请，从而使该技术在项目成功完成后迅速进入临床试验。