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

药物在正确的地方

• 批准号: 8435762
• 负责人: Betsy C. Herold
• 金额: $ 267.77万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 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/8435762
• 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 Formulations; Drug Kinetics; Environment; Equilibrium; Exhibits; 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; Tenofovir disoproxil fumarate; Testing; Tissues; Translating; Vagina; Vaginal Ring; Woman; cohort; design; hormonal contraception; inhibitor/antagonist; nonhuman primate; novel; pandemic disease; pharmacodynamic model; pre-clinical; programs; rectal; tissue/cell culture

DESCRIPTION (provided by applicant): 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 ito 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. RELEVANCE: We will advance a combination of potent ARV drugs formulated for sustained intravaginal ring delivery and expand and optimize non-human primate and human cell and tissue culture models to define the pharmacological and physiological parameters that promote HIV prevention. These studies will facilitate the design of IVRs that are capable of delivering well-distributed ARVs to genital tissues under clinical conditions associated with increased HIV risk.

描述（由申请人提供）：艾滋病毒大流行及其给女性带来的负担凸显了有效的暴露前预防 (PrEP) 的迫切需要。我们假设最佳策略需要结合有效的抗逆转录病毒（ARV）药物，这些药物在多个区室（阴道、宫颈和直肠）中具有活性，表现出快速和持续的药代动力学（PK），对多个分支有效，并且是安全的。理想情况下，应优先考虑持续递送制剂，因为事实证明坚持每日或性交依赖性剂量很困难。基于这些概念，该综合临床前/临床计划将重点关注富马酸替诺福韦二吡呋酯 (TDF) 的阴道环 (IVR) 递送，TDF 是更有效的替诺福韦 (TFV) 前药，与马拉韦罗（一种进入抑制剂）或 IQP 组合-0528，一种非核苷逆转录酶和进入抑制剂，我们已成功配制用于 IVR 递送。我们还将研究 GS7340，这是一种正在开发的新型 TFV 前药，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使用的复杂性。不同的临床结果可能反映了剂量（性交依赖与每日）或依从性的差异。然而，其他重要的生物学因素，包括年龄、激素避孕、精液和阴道微生物群，可能会影响生殖器粘膜环境，从而改变药物 PK、抗病毒活性（药效学 (PD)）和对 HIV 的易感性，从而改变保护和预防之间的平衡。感染。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），并在美国和撒哈拉以南非洲女性的特征明确的队列中进行探索性临床研究，以评估临床变量如何调节药物 PK/PD使用新型离体细胞和组织培养模型（项目 2 和 3），并得到生物分析科学核心的支持。我们的目标是持续优化 IVR 提供抗逆转录病毒药物组合，可为高危女性的艾滋病毒感染部位提供保护性药物水平。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。 相关性：我们将推进用于持续阴道环递送的强效抗逆转录病毒药物组合，并扩大和优化非人类灵长类动物和人类细胞和组织培养模型，以确定促进艾滋病毒预防的药理学和生理参数。这些研究将有助于设计能够在与艾滋病毒风险增加相关的临床条件下向生殖组织提供均匀分布的抗逆转录病毒药物的 IVR。