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

艾滋病毒大流行及其给妇女造成的负担突出表明，迫切需要有效的预先暴露。 预防(PrEP)。我们假设，最佳策略将需要结合有效的抗逆转录病毒药物 (抗逆转录病毒药物)在多个间隔(阴道、宫颈和直肠)有效，表现出快速和 持续药代动力学(PK)，对多分支有效，并且是安全的。理想情况下，持久化 应该优先考虑给药配方，因为坚持每天或性交依赖的剂量已被证明 很难。在这些概念的基础上，这个临床前/临床综合计划将重点放在阴道内 替诺福韦(TFV)更有效的前体药物富马酸替诺福韦(TDF)的环状(IVR)递送 与进入抑制剂马拉韦罗或与IQP-0528结合，非核苷逆转录酶和 进入抑制剂，我们已经成功地为IVR提供。我们还将研究较新的GS7340 TFV前药正在开发中，可能会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试验突出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 坚持不懈。然而，其他重要的生物学因素，包括年龄、激素避孕、精液和 阴道微生物区系可能作用于生殖器粘膜环境，改变药物PK，抗病毒活性 (药效学(PD))和艾滋病毒的易感性，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，我们建议对非人类灵长类动物进行密集的PK/PD研究(项目 1)在具有良好特征的美国和撒哈拉以南非洲妇女队列中进行探索性临床研究 使用新的体外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提供支持。我们的目标是优化持续的IVR 提供一种ARV组合，将在高危艾滋病毒感染部位提供保护性药物水平 女人。我们将在一项第一阶段TDF IVR前期研究中，在有感染艾滋病毒风险的妇女中测试PK/PD模型。 所获得的结果将使我们能够为未来的临床研究优化IVR组合。

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.