Clinical Study to Measure Pharmacokinetics, Pharmacodynamics and Safety of a TDF

该计划的最终目标是开发一种阴道内环(IVR)，用于持续输送一种组合杀菌剂，该组合杀菌剂将安全有效地防止人类免疫缺陷病毒(HIV)和单纯疱疹病毒(HSV)的性传播。安全有效的杀微生物剂可能需要在当地持续提供针对艾滋病毒生命周期不同步骤的抗逆转录病毒药物的组合，以及克服与坚持有关的挑战的给药系统。这将通过逆转录酶抑制剂富马酸替诺福韦(TDF)和进入抑制剂马拉韦罗(MVC)的IVR配方来实现。寻求这种结合的理由是基于CAPRISA 004最近令人振奋的结果，其中1%的TFV凝胶对HIV-1和HSV-2具有显著的保护作用。项目1和2中正在进行的工作表明，与TFV IVR相比，TDF具有潜在的优势，包括更强大的抗艾滋病毒和HSV活性，更强的组织渗透性，以及成功开发出TDF的聚氨酯(PU)IVR配方。在这个新的项目中，一项探索性的前期I期研究被提出，以严格测量健康女性环状分娩后TDF的药代动力学(PK)、药效学(PD)和安全性。要测量的主要结果是TDF释放到生殖道的PK和不良事件。将通过测量生殖道分泌物(腔)和组织中的抗病毒活性(艾滋病毒和HSV)来评估PD 在IVR交付TDF之后。宫颈外组织将在体外用病毒挑战，以评估药物的生物利用度和活性。PU IVRs对粘膜免疫环境的影响将通过量化生殖道中的免疫细胞数量以及生殖道分泌物中炎症、抗炎和可溶性粘膜免疫介质的浓度来评估。将使用先进的分子微生物学工具，包括广泛的16S rRNA基因聚合酶链式反应和焦磷酸测序来确定细菌群落，以及荧光原位杂交来确定环是否改变上皮并导致 阴道生物膜的形成。研究结果将为TDF-MVC联合IVR第一阶段试验的设计提供依据。

The ultimate goal of this Program is to develop an intravaginal ring (IVR) for sustained delivery of a combination microbicide that will be safe and effective in preventing the sexual transmission of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). A safe and effective microbicide will likely require sustained, local delivery of a combination of antiretroviral drugs that target different steps in the HIV life cycle and a delivery system that overcomes the challenges related to adherence. This will be accomplished through IVR formulation of the reverse transcriptase inhibitor, tenofovir disoproxil fumarate (TDF), combined with the entry inhibitor, maraviroc (MVC). The rationale for pursuing this combination is based on the recent promising results of CAPRISA 004 in which significant protection against HIV-1 and HSV-2 was observed with 1% TFV gel. Ongoing work in Projects 1 and 2 demonstrate potential advantages of a TDF compared to a TFV IVR, including more potent activity against HIV and HSV, greater tissue permeability, and the successful development of a polyurethane (PU) IVR formulation of TDF. An exploratory pre-Phase I study is proposed in this new Project to rigorously measure the pharmacokinetics (PK), pharmacodynamics (PD) and safety of TDF following ring delivery in healthy women. The primary outcomes to be measured are PK of TDF release into the genital tract and adverse events. PD will be evaluated by measuring the antiviral activity (HIV and HSV) in genital tract secretions (luminal) and tissue following IVR delivery of TDF. Ectocervical tissue will be challenged ex vivo with virus to assess drug bioavailability and activity. The impact of PU IVRs on the mucosal immune environment will be assessed by quantifying immune cell populations in the genital tract and concentrations of inflammatory, anti-inflammatory and soluble mucosal immune mediators in genital tract secretions. Advanced molecular microbiological tools will be employed including broad range 16S rRNA gene PCR with pyrosequencing to define the bacterial communities, and fluorescence in situ hybridization to determine if rings alter the epithelium and lead to vaginal biofilm formation. Results will inform the design of a Phase I trial of a TDF-MVC combination IVR.