LASER ART for PreP

PreP 激光艺术

基本信息

批准号：
10259156
负责人：
Benson Edagwa
金额：
$ 71.02万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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：
2021-04-12 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10259156
关键词：
AIDS prevention Adherence Adverse event Animal Model Animals Anti-Retroviral Agents Area Arts Biological Availability Biological Models CD4 Positive T Lymphocytes Cell Count Cells Characteristics Chemicals Chemistry Conscious Creativeness Data Data Set Development Dose Drug Design Drug Formulations Drug Kinetics Drug or chemical Tissue Distribution Esterification Esters Female Formulation Freeze Drying Frequencies Funding Future Gap Junctions Goals HIV Infections HIV-1 Half-Life Health Healthcare Hematology Histology Human Hydrolysis Hydrophobicity Immunologics Individual Industry Infection Injections Interdisciplinary Study Intramuscular Injections Investigational New Drug Application Laboratories Lasers Lead Letters Life Link Lipids Macaca mulatta Measures Medicine Metabolic Modification Mus Names Nebraska Nucleotides Pathway interactions Penetrance Personal Satisfaction Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacy (field)Plants Plasma Powder dose form Preclinical Testing Prevention Process Prodrugs Production Publications Publishing Quality Control Rattus Reproducibility Research Research Design Research Personnel Research Project Grants Rest Reticuloendothelial System Rodent Safety Savings Scheme Science Scientist Sex Differences Site Substance Use Disorder Suspensions Tenofovir Test Result Testing Tissues Toxicology Treatment Protocols United States Food and Drug Administration Universities Validation Viral Load result Viral reservoir Virus Virus Replication Work antiretroviral therapy base bench to bedside biomaterial compatibility chemical synthesis cost design disease transmission drug modification emtricitabine expectation high risk humanized mouse improved innovation interdisciplinary approach large scale production lipophilicity macrophage male multidisciplinary nanocrystal nanoformulation nanomedicine novel novel strategies nucleoside monophosphate particle pharmacokinetics and pharmacodynamics pill pre-exposure prophylaxis prevent product development scale up surfactant tool translational study uptake viral resistance viral transmission virology

项目摘要

Abstract This project contains a highly collaborative investigative team with interdisciplinary expertise with significant potential impact for HIV/AIDS prevention. The proposal includes pharmacologic, virologic, animal and product development studies designed to halt disease transmission through novel long-acting (LA) antiretrovirals. These are named LA slow effective release antiretroviral therapies (LASER ART) designed to facilitate HIV-1 prevention by intense bench to the clinic translational studies. Innovative interdisciplinary approaches contain a detailed research plan, extensive preliminary and broadly published supportive data. Creativity and innovativeness are offered placed at higher risk than a conventional research project. The work builds on the development of parenteral nanoformulations of chemically modified antiretroviral drugs designed to improve adherence. The drugs are currently offered once/day in pill form but will be converted to up to once a year administration. Support from expert pharmacologists and pharmaceutical scientists with University researchers are operative. The drugs include dolutegravir (DTG), emtricitabine (FTC) and tenofovir (TFV) created to extend their apparent drug half-life, efficacy and abilities to target viral reservoirs. They are, in measure, DTG and FTC and TFV prodrug + nucleotide (ProTides) designated “N” for nanoformulation, “M” for esterification and “P” for ProTides. The created NPFTC and NPTFV and NM2DTG demonstrate sustained plasma and tissue drug concentrations of > 90% inhibitory concentration from months to a year. Based on encouraging results, we seek funds to facilitate large scale development that would facilitate future human studies. The final formulations would be characterized by sustained prodrug hydrolysis with reduced injection volumes. The pathway forward follows established partnership with the Clinton Health Access Initiative and oversight by ViiV Healthcare and Gilead Sciences. The overarching goal is safety, reproducibility and “scale-up” that follows US Food and Drug Administration-approved current good manufacturing practices (cGMP). The specific aims are each supported by extensive published data sets forged through the multidisciplinary research. Creation and characterization focus on prodrug formulations, toxicology, and pharmacokinetics profiles follow a safe developmental action plan. The work is facilitated by a fully operational cGMP facility and rhesus macaque validations. The lead formulation will be developed with our CHAI partners. We posit that the creation of LASER ART DTG or FTC and TFV will have a profound impact on HIV prevention.

抽象的该项目包含一个高度协作的调查团队，具有跨学科的专业知识，具有重要的该提案包括药理学、病毒学、动物和产品的潜在影响。旨在通过新型长效（LA）抗逆转录病毒药物阻止疾病传播的开发研究。这些被命名为 LA 缓慢有效释放抗逆转录病毒疗法 (LASER ART)，旨在促进 HIV-1 通过深入的临床转化研究进行预防包括创新的跨学科方法。详细的研究计划、广泛的初步和广泛发表的支持性数据以及创造力。与传统研究项目相比，创新的风险更高。开发化学修饰的抗逆转录病毒药物的肠外纳米制剂，旨在改善这些药物目前以药丸形式每天提供一次，但将改为每年一次。专家药理学家和药物科学家以及大学研究人员的支持。这些药物包括多替拉韦（DTG）、恩曲他滨（FTC）和替诺福韦（TFV）。它们的表观药物半衰期、功效和针对病毒库的能力在某种程度上是 DTG 和 FTC。 TFV 前药 + 核苷酸 (ProTides)，纳米制剂指定为“N”，酯化指定为“M”，酯化指定为“P” ProTides 所创建的 NPFTC 和 NPTFV 以及 NM2DTG 展示了持续的血浆和组织药物。基于令人鼓舞的结果，我们从几个月到一年的时间里抑制浓度> 90%。寻求资金促进大规模开发，以促进未来的人类研究。制剂的特点是持续前药水解并减少注射量。前进的道路遵循与克林顿健康访问计划建立的合作伙伴关系以及 ViiV 的监督医疗保健和吉利德科学的首要目标是遵循美国的安全性、可重复性和“规模化”。美国食品和药物管理局批准的现行良好生产规范 (cGMP) 的具体目标是。每个都得到了通过多学科研究形成的广泛发布的数据集的支持。表征重点关注前药配方、毒理学和药代动力学特征，遵循安全标准全面运作的 cGMP 设施和恒河猴促进了这项工作。我们将与我们的 CHAI 合作伙伴一起开发主要配方。激光艺术 DTG 或 FTC 和 TFV 将对艾滋病毒预防产生深远影响。