The overarching purpose of this Center Grant, """"""""Alternative Formulations of Tenofovir and UC781"""""""" is to develop and compare the performance of two contrasting vaginal microbicide formulation approaches, a gel and a film, as carriers for an antiretroviral drug combination, UC781 and tenofovir (TFV). This project, Project 4, quantitatively explores the PK domain in exploratory clinical studies by way of direct and non-invasive sampling of 6 different compartments within the body - fluid and CD4+ cells components both within the cervicovaginal lumen, cervicovaginal tissues, and blood. The spatlotemporal drug concentration data gathered will be evaluated in light of pharmacodynamic (PD) data, both efficacy and toxicity, from this and other Projects within the Center Grant. Armed with this PK-PD data investigators can reach informed decisions about (1) continued development of these two combination products, (2) potential modifications of the eventual product candidates tested, and (3) rational study design as the candidates enter formal clinical testing. To achieve these objective, we have the following 4 specific aims:
Aim 1. Develop and validate assays for UC781, improve tenofovir intracellular assay sensitivity in clinical samples, and verify compatibility of radiolabels with film formulations (Supports Aim 3 &4 clinical studies) Aim 2. Determine the feasibility of using quantitative changes in cervicovaginal permeability to small molecules and HIV-size particles as a measure of candidate microbicide toxicity: an open label, exploratory clinical study comparing nonoxynol-9 gel to universal placebo. (Needed for support of Specific Aim 3).
Aim 3. Compare the spatlotemporal distribution (cervicovaginal and systemic) of candidate film and gel formulations of UC781 (Aim 3-1) and TFV (Aim 3-2): an exploratory clinical study.
Aim 4. Exploratory Human and Macaque PK-PD relationships. Perform drug assays from pharmacodynamic (efficacy and toxicity) studies in macaques (Project 2) and humans (Project 3) and develop exploratory pharmacokinetic-pharmacodynamic (PK-PD) models to describe the drug exposure-response relationships for each candidate microbicide (UC781 and tenofovir) and formulation.

Public Health Relevance

Success with these aims will describe female genital tract and systemic drug distribution and correlations between drug concentration at the site of action and drug effect, both salutory and toxic. This data will greatly inform decisions regarding future development and clinical study designs to move more efficiently and rationally toward development of a much needed vaginal combination antiretroviral microbicide film.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Magee-Women's Research Institute and Foundation
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Guthrie, K M; Rohan, L; Rosen, R K et al. (2018) Vaginal film for prevention of HIV: using visual and tactile evaluations among potential users to inform product design. Pharm Dev Technol 23:311-314
Grab, Sheila; Rohan, Lisa C (2018) A Quantitative Disintegration Method for Polymeric Films. J Pharm Innov 13:321-329
Robinson, Jennifer A; Marzinke, Mark A; Fuchs, Edward J et al. (2018) Comparison of the Pharmacokinetics and Pharmacodynamics of Single-Dose Tenofovir Vaginal Film and Gel Formulation (FAME 05). J Acquir Immune Defic Syndr 77:175-182
Richardson-Harman, Nicola; Parody, Robert; Anton, Peter et al. (2017) Analytical Advances in the Ex Vivo Challenge Efficacy Assay. AIDS Res Hum Retroviruses 33:395-403
Robinson, Jennifer A; Marzinke, Mark A; Bakshi, Rahul P et al. (2017) Comparison of Dapivirine Vaginal Gel and Film Formulation Pharmacokinetics and Pharmacodynamics (FAME 02B). AIDS Res Hum Retroviruses 33:339-346
Beamer, May A; Austin, Michele N; Avolia, Hilary A et al. (2017) Bacterial species colonizing the vagina of healthy women are not associated with race. Anaerobe 45:40-43
Patel, Sravan Kumar; Rohan, Lisa Cencia (2017) On-demand microbicide products: design matters. Drug Deliv Transl Res 7:775-795
Petrina, Melinda A B; Cosentino, Lisa A; Rabe, Lorna K et al. (2017) Susceptibility of bacterial vaginosis (BV)-associated bacteria to secnidazole compared to metronidazole, tinidazole and clindamycin. Anaerobe 47:115-119
Fan, Maria D; Kramzer, Lindsay F; Hillier, Sharon L et al. (2016) Preferred Physical Characteristics of Vaginal Film Microbicides for HIV Prevention in Pittsburgh Women. Arch Sex Behav :
Hu, Minlu; Zhou, Tian; Pearlman, Andrew P et al. (2016) Comparative Expression Analysis of Cytochrome P450 1A1, Cytochrome P450 1B1 and Nuclear Receptors in the Female Genital and Colorectal Tissues of Human and Pigtailed Macaque. BAOJ Pharm Sci 2:

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