Novel Determination of Microbicide PK in Women's Reproductive Health

描述（由申请人提供）：阴道杀微生物剂提供了很大的希望，以防止艾滋病毒的性传播。产品（活性药物成分+剂型）的药代动力学（PK）对于预防功能（PD）至关重要。但我们测量的能力 并预测杀微生物剂PK目前是有限的。此外，杀微生物剂PD取决于产品+剂量方案如何适应阴道环境的一系列条件。这些都是在内分泌控制下，包括阴道粘膜的状态（上皮结构，厚度，液体等）。它们因月经周期、产次、微生物学、绝经和生殖健康方面的其他因素而异。所有这些群体中的妇女都需要杀微生物剂！但有效的产品设计和应用的细节可能会有所不同的分组。为此，我们将创建/应用新的方法来测量，预测和解释关键的，前所未有的杀微生物剂的PK数据，在生物学上不同的阴道环境的背景下。我们将创建一个光学成像平台，用于实用，敏锐，无活检阴道内测量妇女的3D浓度分布的杀微生物剂活性成分（API）-使用新的多模态共焦拉曼光谱。该仪器同时测量整个阴道的局部上皮厚度分布-使用定制的、共配准的谱域光学相干断层扫描（SD-OCT）。因此，API浓度和阴道粘膜结构的3D图在API作用的整个空间中相关联。我们将建立和应用这种仪器在妇女的替诺福韦（领先的API）凝胶或阴道环（领先的剂型）提供的分析。数据将与我们将创建的API递送的新的、新的房室模型的预测进行比较。具体目标：（1）构建、评价性能并应用双传感阴道内光学成像装置，以三维方式测量通过凝胶和环递送到腔液和下层组织的杀微生物剂API的人阴道周围浓度（使用共焦多模式拉曼光谱法）。包括定制的共配准SD-OCT以定位上皮表面并测量其局部厚度;（2）构建新光学装置的临床原型并对由临床凝胶或环递送的替诺福韦分布进行体内人体成像研究。将结果与传统的从阴道灌洗和活检收集的（和有限的）P数据;将所有结果与局部阴道组织特征相关联;分析月经周期、产次、微生物学环境和围绝经期的不同阶段的影响;（三）创建并应用通过阴道凝胶和环向腔液和组织递送杀微生物剂API的机械计算房室模型，并比较模型预测与PK来自临床研究的数据（成像，传统）。因此，加深对杀微生物剂PK的多因素决定因素的理解。扩展这些知识，以帮助解释当前杀微生物剂产品和剂量方案的范围，并帮助指导下一代改良杀微生物剂产品的合理开发。

DESCRIPTION (provided by applicant): Vaginal microbicides offer much promise to prevent sexual transmission of HIV. The pharmacokinetics (PK) of a product (active pharmaceutical ingredient + dosage form) is central to prophylactic functionality (PD). But our ability to measure and predict microbicide PK is currently limited. Further, microbicide PD depends on how product + dosage regimen accommodate a range of conditions of the vaginal environment. These are under endocrine control, which includes the state of the vaginal mucosa (epithelial architecture, thickness, fluid, etc). They vary with menstrual cycle phase, parity, microbiology, menopause and other factors in reproductive health. Women in all these groupings need microbicides! But details of efficacious product design and application may differ amongst the groupings. To this end, we will create/apply novel methodology to measure, predict and interpret critical, unprecedented PK data for microbicides, in the context of the biologically varying vaginal environment. We will create an optical imaging platform for practical, incisive, biopsy-free intravaginal measurement in women of 3D concentration distributions of microbicide active ingredients (APIs) - using novel multimodal confocal Raman spectroscopy. The instrument simultaneously measures local epithelial thickness distribution throughout the vagina - using customized, co-registered spectral domain optical coherence tomography, SD-OCT. Thus, 3D maps of API concentration and vaginal mucosal architecture are linked, throughout the space where APIs act. We will build and apply this instrument in women for analysis of tenofovir (a leading API) delivered by a gel or intravaginal rings (leading dosage forms). Data will be compared to predictions of novel, new compartmental models of API delivery which we will create. Specific Aims: (1) Construct, evaluate performance and apply a dual sensing intra-vaginal optical imaging device to measure, in three dimensions, human peri-vaginal concentrations of microbicide APIs (using confocal multimodal Raman spectroscopy) delivered to luminal fluids and underlying tissues by gels and rings. Include customized co- registered SD-OCT to locate the epithelial surface and measure its local thickness; (2) Construct a clinical prototype of the new optical device and perform in vivo human imaging studies for tenofovir distributions delivered by a clinical gel or ring. Compare results with traditional (and limited) P data collected from vaginal lavage and biopsies; relate all results to local vaginal tissue characteristics; analyze effects of different phases of the menstrual cycle, parity, microbiologica milieu and peri-menopause; (3) Create and apply mechanistic computational compartmental models of microbicide API delivery by vaginal gels and rings to luminal fluids and tissues and compare model predictions with PK data (imaging, traditional) from the clinical studies. Consequently, develop enhanced understanding of the multifactorial determinants of microbicide PK. Extend this knowledge to help interpret the spectrum of current microbicide products and dosage regimens, and to help guide rational creation of the next generation of improved microbicide products.