Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring PrEP

药物在正确的地方

• 批准号: 8988532
• 负责人: Betsy C. Herold
• 金额: $ 265.22万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8988532
• 关键词: AIDS prevention; Address; Adherence; African; Age; Anti-Retroviral Agents; Antiviral Agents; Biological Factors; Cervical; Clinical; Clinical Research; Conflict (Psychology); Data; Development; Dose; Drug Kinetics; Environment; Equilibrium; Exhibits; Formulation; Fumarates; Future; Genital system; Goals; HIV; HIV Infections; HIV risk; High Risk Woman; Human; Infection; Knowledge; Lymphoid Tissue; Modeling; Oral; Outcome; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiological; Predisposition; Prodrugs; Prophylactic treatment; Protective Agents; RNA-Directed DNA Polymerase; Risk; Seminal fluid; Site; Tenofovir; Testing; Tissues; Translating; Vagina; Vaginal Ring; Woman; cohort; design; hormonal contraception; inhibitor/antagonist; microbiota; nonhuman primate; novel; pandemic disease; pharmacodynamic model; pre-clinical; programs; rectal; tissue/cell culture

The HIV pandemic and its burden on women highlights the urgent need for effective pre-exposure prophylaxis (PrEP). We hypothesize that the optimal strategy will require combining potent antiretroviral (ARV) drugs that are active in multiple compartments (vaginal, cervical, and rectal), exhibit rapid and sustained pharmacokinetics (PK), are effective against multiple clades, and are safe. Ideally, sustained delivery formulations should be prioritized, as adherence to daily or coitally dependent dosing has proven difficult. Building from these concepts, this Integrated Preclinical/Clinical Program will focus on intravaginal ring (IVR) delivery of tenofovir disoproxil fumarate (TDF), the more potent prodrug of tenofovir (TFV), in combination with maraviroc, an entry inhibitor, or with IQP-0528, a non-nucleoside reverse transcriptase and entry inhibitor that we have successfully formulated for IVR delivery. We will also study GS7340, a newer TFV prodrug in development, with potentially better distribution into lymphoid tissues. The conflicting results of recent topical and oral PrEP trials highlight the complexities in translating preclinical data into real world use. The variable clinical outcomes may reflect differences in dosing (coitally dependent vs. daily) or in adherence. However, other important biological factors, including age, hormonal contraception, semen and vaginal microbiota may have acted on the genital mucosal environment to alter drug PK, antiviral activity (pharmacodynamics (PD)), and susceptibility to HIV, shifting the balance between protection and infection. To address this critical knowledge gap, we propose intensive PK/PD studies in non-human primates (Project 1) and exploratory clinical studies in well-characterized cohorts of U.S. and sub-Saharan African women to assess how clinical variables modulate drug PK/PD using novel ex vivo cell and tissue culture models (Projects 2 and 3), supported by a bioanalytical scientific core. Our goal is to optimize sustained IVR delivery of an ARV combination that will provide protective drug levels at the sites of HIV infection in high risk women. We will test a PK/PD model in a pre-Phase I TDF IVR study in women at risk for HIV acquisition. Results obtained will enable us to optimize IVR combinations for future clinical studies.

艾滋病毒大流行及其给妇女带来的负担凸显了有效预暴露的迫切需要 预防（PrEP）。我们假设最佳策略需要结合有效的抗逆转录病毒药物 (ARV) 药物在多个室（阴道、宫颈和直肠）中具有活性，表现出快速且有效的作用。 持续的药代动力学（PK），对多个进化枝有效，并且是安全的。理想情况下，持续 应优先考虑递送配方，因为已证明坚持每日或性交依赖性剂量 难的。基于这些概念，该综合临床前/临床计划将重点关注阴道内 富马酸替诺福韦二吡呋酯 (TDF) 的环 (IVR) 递送，TDF 是替诺福韦 (TFV) 的更有效的前药， 与马拉韦罗（一种进入抑制剂）或与 IQP-0528（一种非核苷逆转录酶）组合 我们已成功配制用于 IVR 递送的进入抑制剂。我们还将研究 GS7340，一种较新的 TFV 前药正在开发中，有可能更好地分布到淋巴组织中。相互矛盾的结果 最近的局部和口服 PrEP 试验凸显了将临床前数据转化为现实世界的复杂性 使用。不同的临床结果可能反映了剂量的差异（性交依赖与每日）或 坚持。然而，其他重要的生物因素，包括年龄、激素避孕、精液和 阴道微生物群可能作用于生殖器粘膜环境，改变药物 PK 和抗病毒活性 （药效学 (PD)）和对 HIV 的易感性，改变了保护和感染之间的平衡。 为了解决这一关键的知识差距，我们建议在非人类灵长类动物中进行深入的 PK/PD 研究（项目 1) 以及在美国和撒哈拉以南非洲女性的特征明确的队列中进行的探索性临床研究 使用新型离体细胞和组织培养模型评估临床变量如何调节药物 PK/PD （项目 2 和 3），由生物分析科学核心支持。我们的目标是优化持续的 IVR 提供抗逆转录病毒药物组合，为高危艾滋病毒感染部位提供保护性药物水平 女性。我们将在 I 期前 TDF IVR 研究中对有 HIV 感染风险的女性测试 PK/PD 模型。 获得的结果将使我们能够优化未来临床研究的 IVR 组合。