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.
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.
|Akil, Ayman; Agashe, Hrushikesh; Dezzutti, Charlene S et al. (2015) Formulation and characterization of polymeric films containing combinations of antiretrovirals (ARVs) for HIV prevention. Pharm Res 32:458-68|
|Rinehart, Matthew; Grab, Sheila; Rohan, Lisa et al. (2014) Analysis of vaginal microbicide film hydration kinetics by quantitative imaging refractometry. PLoS One 9:e95005|
|Zhou, Tian; Hu, Minlu; Pearlman, Andrew et al. (2014) Expression and localization of p-glycoprotein, multidrug resistance protein 4, and breast cancer resistance protein in the female lower genital tract of human and pigtailed macaque. AIDS Res Hum Retroviruses 30:1106-16|
|Akil, Ayman; Devlin, Brid; Cost, Marilyn et al. (2014) Increased Dapivirine tissue accumulation through vaginal film codelivery of dapivirine and Tenofovir. Mol Pharm 11:1533-41|
|Chappell, Catherine A; Rohan, Lisa C; Moncla, Bernard J et al. (2014) The effects of reproductive hormones on the physical properties of cervicovaginal fluid. Am J Obstet Gynecol 211:226.e1-7|
|Parsons, Teresa L; Emory, Joshua F; Seserko, Lauren A et al. (2014) Dual quantification of dapivirine and maraviroc in cervicovaginal secretions from ophthalmic tear strips and polyester-based swabs via liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis. J Pharm Biomed Anal 98:407-16|
|Dezzutti, Charlene S; Uranker, Kevin; Bunge, Katherine E et al. (2013) HIV-1 infection of female genital tract tissue for use in prevention studies. J Acquir Immune Defic Syndr 63:548-54|
|Zhou, Tian; Hu, Minlu; Cost, Marilyn et al. (2013) Short communication: expression of transporters and metabolizing enzymes in the female lower genital tract: implications for microbicide research. AIDS Res Hum Retroviruses 29:1496-503|
|Isaacs, Charles E; Xu, Weimin (2013) Theaflavin-3,3'-digallate and lactic acid combinations reduce herpes simplex virus infectivity. Antimicrob Agents Chemother 57:3806-14|
|Rinehart, Matthew T; Drake, Tyler K; Robles, Francisco E et al. (2011) Time-resolved imaging refractometry of microbicidal films using quantitative phase microscopy. J Biomed Opt 16:120510|