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Novel Determination of Microbicide PK in Women's Reproductive Health

女性生殖健康中杀菌剂 PK 的新测定

基本信息

批准号：
8829030
负责人：
DAVID Frank KATZ
金额：
$ 42.48万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8829030
关键词：
AIDS prevention Affect Architecture Biological Factors Biopsy Blood Characteristics Clinical Clinical Research Clinical Trials Complex Contraceptive methods Data Development Devices Dimensions Dosage Forms Drug Delivery Systems Drug Kinetics Drug usage Endocrine Environment Epithelial Evaluation Exposure to Female Gel Grouping HIV HIV Entry Inhibitors Human Image Imaging Device In Situ Infection Irrigation Knowledge Label Link Liquid substance Local Microbicides Maps Measurement Measures Mediating Menopause Menstrual cycle Methodology Methods Microbiology Modeling Mucous Membrane Nature Optical Coherence Tomography Optics Oral Performance Permeability Pharmaceutical Preparations Pharmacologic Substance Phase Physiological Predisposition Property Raman Spectrum Analysis Regimen Reproductive Health Reproductive Physiology Sampling Science Serum Site Surface TMC120-R147681 Techniques Technology Tenofovir Thick Time Tissues Transvaginal Ultrasound Vagina Vaginal Douching Vaginal Gel Vaginal Ring Variant Woman anti-HIV microbicide design dosage drug distribution experience imaging platform improved in vivo instrument microbicide next generation novel optical imaging parity pharmacokinetic model practical application prevent product development prophylactic prototype reproductive sexual HIV transmission success transmission process vaginal fluid vaginal microbicide

项目摘要

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.

描述（由申请人提供）：阴道杀菌剂对预防艾滋病毒的性传播大有希望。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。但是我们测量的能力