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：
9089920
负责人：
Marc Michael Baum
金额：
$ 81.29万
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/9089920
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 Development Devices Dimensions Diphosphates Dose Drug Delivery Systems Drug Exposure Drug Kinetics Drug or chemical Tissue Distribution Formulation Frequencies Goals HIV HIV-1 Half-Life Health 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 Lead 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 Process 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 experience flexibility humanized mouse improved in vivo manufacturing process meetings models and simulation nanoformulation nanoparticle non-nucleoside reverse transcriptase inhibitors novel particle pharmacodynamic model pre-clinical prevent prototype 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（由适用提供）：遵守每日给药方案已成为推动HIV-1预防前预防（PREP）抗逆转录病毒（ARV）药物的关键因素。可以通过持续释放或“长效” ARV公式来减轻这种挑战，以降低给药频率，理想情况下每月或更长时间间隔一次。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；注射后不能去除颗粒不良反应；该方法需要特定的ARV理化特征，从而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，使用核侧逆转录酶抑制剂（NRTI）Tenofovir（TFV）的制剂的PREP可以防止在很大比例的个体中预防HIV-1感染。用于全身剂量的长效TFV公式将为持续发布准备选项的投资组合增加急需的NRTI。 TFV对支持HIV-1复制的免疫细胞和该药物高水溶性的生物利用度的低生物利用度使得开发了长效公式极为挑战。我们的建议通过使用从新颖，获得专利的皮下植入物技术提供的高效前药TFV Alafenamide（TAF）来克服这些障碍，该技术提供了线性释放动力学，没有初始爆发效果。在初步研究中，我们开发了一种原型TAF植入物，并在40天内评估了其在Beagle犬中的药代动力学（PKS）。该植入物在外周血单核细胞中维持稳态的TFV二磷酸（TFV-DP），该药物的活性代谢物，比推定的HIV-1预防性预防的稳态。拟议的努力以这些重要的结果为基础，并将检验中心假设，即具有实际物理维度的一年TAF植入物可以安全防止性HIV-1感染。在AIM 1中，我们将设计TAF在小鼠，狗和猕猴中进行剂量范围研究。我们将与CMO合作转移制造技术，以在项目五年期结束时建立根据CGMP制造Imprans的能力。在AIM 2中，我们将评估小鼠，狗和猕猴模型中原型的PK和安全性。矩阵辅助激光取消成像质谱法将用于确定阴道和直肠组织中TFV和TFV-DP的3D分布。总之，这些基本科学研究将使我们能够开发人类PK模拟模型，从而可以预测相应的体外数据中体内释放速率。在AIM 3中，将在人源化的小鼠和猕猴中进行HIV-1预防效率研究，从而可以在探索性模型中研究PK-Pharmacodynalnegantials的关系。上述活动将以里程碑为驱动，最终通过向美国FDA提交了调查新药（IND）申请，从而使该技术成功完成后，该技术能够迅速发展临床试验。