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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZHD1-DSR-W (50))
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Zajicek, Anne
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Duke University
Biomedical Engineering
Schools of Engineering
United States
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Chuchuen, Oranat; Maher, Jason R; Henderson, Marcus H et al. (2017) Label-free analysis of tenofovir delivery to vaginal tissue using co-registered confocal Raman spectroscopy and optical coherence tomography. PLoS One 12:e0185633
Gao, Yajing; Katz, David F (2017) Multicompartmental Pharmacokinetic Model of Tenofovir Delivery to the Rectal Mucosa by an Enema. PLoS One 12:e0167696
Chuchuen, Oranat; Maher, Jason R; Simons, Morgan G et al. (2017) Label-Free Measurements of Tenofovir Diffusion Coefficients in a Microbicide Gel Using Raman Spectroscopy. J Pharm Sci 106:639-644
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Katz, David F; Yuan, Andrew; Gao, Yajing (2015) Vaginal drug distribution modeling. Adv Drug Deliv Rev 92:2-13
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Maher, Jason R; Matthews, Thomas E; Reid, Ashley K et al. (2014) Sensitivity of coded aperture Raman spectroscopy to analytes beneath turbid biological tissue and tissue-simulating phantoms. J Biomed Opt 19:117001
Chuchuen, Oranat; Henderson, Marcus H; Sykes, Craig et al. (2013) Quantitative analysis of microbicide concentrations in fluids, gels and tissues using confocal Raman spectroscopy. PLoS One 8:e85124

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