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

描述（由申请人提供）：艾滋病毒大流行及其对妇女的负担突出了对有效的暴露前预防（PrEP）的迫切需要。我们假设，最佳策略将需要联合有效的抗逆转录病毒（ARV）药物，这些药物在多个隔室（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，应优先考虑持续给药制剂，因为坚持每日或性交依赖性给药已被证明是困难的。基于这些概念，该综合临床前/临床项目将重点关注替诺福韦酯富马酸酯（TDF）（替诺福韦（TFV）的更有效前药）与马拉韦罗（一种进入抑制剂）或IQP-0528（一种非核苷逆转录酶和进入抑制剂）的阴道环（IVR）递送，我们已成功地为IVR递送配制。我们还将研究GS 7340，一种正在开发的较新的TFV前药，可能更好地分布到淋巴组织中。矛盾的结果 最近的局部和口服PrEP试验强调了将临床前数据转化为真实的世界使用的复杂性。不同的临床结局可能反映了给药（依赖性交vs.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对生殖器粘膜环境起作用，改变药物PK、抗病毒活性（药效学（PD））和对HIV的易感性，改变保护和感染之间的平衡。为了解决这一关键的知识差距，我们建议在非人灵长类动物中进行密集的PK/PD研究（项目1），并在美国和撒哈拉以南非洲妇女的良好特征队列中进行探索性临床研究，以评估临床变量如何使用新型离体细胞和组织培养模型调节药物PK/PD（项目2和3），并得到生物分析科学核心的支持。我们的目标是优化持续的 IVR提供抗逆转录病毒药物组合，在高危妇女的艾滋病毒感染部位提供保护性药物水平。我们将在有HIV感染风险的女性中进行的I期前TDF IVR研究中测试PK/PD模型。获得的结果将使我们能够优化IVR组合，用于未来的临床研究。 相关性：我们将推进一种有效的抗逆转录病毒药物组合，用于持续的阴道环内递送，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学参数。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将分布良好的抗逆转录病毒药物输送到生殖器组织的IVRs。

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.