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.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082639-05
Application #
8660270
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Magee-Women's Research Institute and Foundation
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
Moncla, Bernard J; Chappell, Catherine A; Debo, Brian M et al. (2016) The Effects of Hormones and Vaginal Microflora on the Glycome of the Female Genital Tract: Cervical-Vaginal Fluid. PLoS One 11:e0158687
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Zhou, Tian; Hu, Minlu; Pearlman, Andrew et al. (2016) Expression, regulation, and function of drug transporters in cervicovaginal tissues of a mouse model used for microbicide testing. Biochem Pharmacol 116:162-75
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 :
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Moncla, Bernard J; Chappell, Catherine A; Mahal, Lara K et al. (2015) Impact of bacterial vaginosis, as assessed by nugent criteria and hormonal status on glycosidases and lectin binding in cervicovaginal lavage samples. PLoS One 10:e0127091
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Hu, Minlu; Patel, Sravan Kumar; Zhou, Tian et al. (2015) Drug transporters in tissues and cells relevant to sexual transmission of HIV: Implications for drug delivery. J Control Release 219:681-96
Wang, Linlin; Koppolu, Sujeethraj; Chappell, Catherine et al. (2015) Studying the effects of reproductive hormones and bacterial vaginosis on the glycome of lavage samples from the cervicovaginal cavity. PLoS One 10:e0127021
Chappell, Catherine A; Isaacs, Charles E; Xu, Weimin et al. (2015) The effect of menopause on the innate antiviral activity of cervicovaginal lavage. Am J Obstet Gynecol 213:204.e1-6

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