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

说明（由申请人提供）：艾滋病毒大流行及其对妇女造成的负担突出表明迫切需要有效的接触前预防。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，这些药物在多个腔室（阴道、宫颈和直肠）起作用，表现出快速和持续的药代动力学（PK），对多种分支有效，并且安全。理想情况下，应优先考虑持续给药配方，因为坚持每日或性交依赖剂量已被证明是困难的。基于这些概念，这个综合临床前/临床项目将专注于阴道内环（IVR）递送替诺福韦（TDF），这是替诺福韦（TFV）更有效的前药，与马拉维洛克（一种进入抑制剂）或与IQP-0528（一种非核苷逆转录酶和进入抑制剂，我们已经成功地为IVR递送配方）联合。我们还将研究GS7340，这是一种正在开发的较新的TFV前药，可能更好地进入淋巴组织。相互矛盾的结果

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.