Novel Determination of Microbicide PK in Women's Reproductive Health

描述(由申请人提供)：阴道杀菌剂为防止艾滋病毒的性传播提供了很大的希望。产品(活性药物成分+剂型)的药代动力学(PK)是预防功能(PD)的核心。但我们测量的能力 并预测杀菌剂PK目前有限。此外，杀菌剂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)。它们因月经周期阶段、产次、微生物学、绝经和其他生殖健康因素而异。所有这些群体中的女性都需要杀微生物剂！但有效产品设计和应用的细节可能在不同的集团之间有所不同。为此，我们将创建/应用新的方法来测量、预测和解释关键的、史无前例的杀菌剂PK数据，在生物多样性的阴道环境中。我们将创建一个光学成像平台，使用新的多模共聚焦拉曼光谱，实用、深入、无需活检的女性阴道内测量杀菌剂活性成分(APIs)的3D浓度分布。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、共同注册的光谱域光学相干断层扫描，SD-OCT。因此，原料药浓度和阴道粘膜结构的3D地图被联系在一起，贯穿原料药发挥作用的空间。我们将在女性中建立和应用这一仪器，用于分析替诺福韦(一种主要的原料药)，通过凝胶或阴道内环(主要剂型)传递。数据将与我们将创建的新的、新的API交付间隔模型的预测进行比较。具体目标：(1)构建、评估性能并应用双传感阴道内光学成像设备，以三维方式测量人体阴道周围通过凝胶和环向腔液和下层组织输送的杀微生物剂原料药的浓度(使用共聚焦多模拉曼光谱)。包括定制的联合注册SD-OCT，以定位上皮表面并测量其局部厚度；(2)构建新型光学设备的临床原型，并对临床凝胶或环传递的替诺福韦分布进行体内人体成像研究。将结果与从阴道冲洗和活检收集的传统(且有限的)P数据进行比较；将所有结果与局部阴道组织特征相关联；分析月经周期不同阶段、产次、微生物环境和围绝经期的影响；(3)创建和应用杀菌剂API通过阴道凝胶和环向腔液和组织输送的机械性计算隔室模型，并将模型预测与临床研究的PK数据(成像、传统)进行比较。因此，加强对杀菌剂PK的多因素决定因素的理解。扩展这一知识以帮助解释当前杀微生物剂产品和剂量方案的范围，并帮助指导合理创造下一代改进的杀微生物剂产品。 公共卫生相关性：妇女生殖健康中杀菌剂PK的新测定。该项目将有助于开发妇女经阴道使用的局部杀微生物剂产品，以抑制艾滋病毒的性传播。它将开发一种新的仪器，获得关于杀菌剂药代动力学(PK)的前所未有的有价值的数据。仪器的测量结果将被输入到新的计算PK模型中。这将适合在临床试验中的实际应用。从而为改进现有杀微生物剂产品的评价和改进产品的开发提供参考。

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. PUBLIC HEALTH RELEVANCE: Novel determination of microbicide PK in women's reproductive health. This project will contribute to the development of topical microbicide products for vaginal application by women to inhibit the sexual transmission of HIV. It will develop a new instrument that will obtain unprecedented and valuable data about microbicide pharmacokinetics (PK). Measurements with the instrument will be input to new computational PK models. This will be suitable for practical application in clinical trials. Thus, it will contriute to improved evaluation of current microbicide products and development of improved ones.