Our overall goal is to optimize hypotonic rectal enema formulations for delivering tenofovir (TFV) and TFV analogs to the entire colorectal surface with as high a dose as can be delivered safely. We have investigated the role of enema vehicle tonicity in drug delivery in the mouse rectum, including hypotonic formulations that cause rapid water uptake from the lumen, and hypertonic formulations that cause rapid secretion of water into the lumen. Our results are consistent with the studies done by Hendrix and coworkers in the human colorectum: (i) tap water, a maximally hypotonic formulation, drives drug delivery and absorption locally, and not as far up the colon as is likely necessary, and (ii) Fleet enema, a markedly hypertonic vehicle, causes fluid secretion that prevents uniform drug distribution. In contrast, moderately hypotonic formulations provide the best surface distribution, and they do so rapidly. Hypotonic formulations deliver drugs and drug-loaded nanocrystals by advection caused by sodium (Na+)-driven, osmotically-induced flow of water from the lumen into the tissues, similar to the natural process by which the colorectum dehydrates the feces. Importantly, relatively high Na+ in semen makes it hypotonic in the colorectum, which is likely to deliver HIV rapidly to the epithelium by advection, thus suggesting that our moderately-hypotonic enema drug delivery method may be critical to ensure that drug is delivered to all surfaces where HIV can reach.
In Aim 1, we will optimize a mildly hypotonic formulation for delivering TFV and TFV analogs to the colorectum of mice, and then in non-human primates (NHP), to select the enhanced bioavailability product to be used in clinical studies in Projects 1 and 4.
In Aim 2, we will be designing an enhanced enema product for increased bioavailability, and sustained drug release.
In Aim 2 A, we will determine whether mucus-penetrating drug nanocrystals can prolong the duration of prophylactic drug concentrations of TFV and TFV analogs in mice, and then in NHP.
In Aim 2 B, we will test the hypothesis that a gelling agent will prolong retention on the colorectal surface, and possibly form a barrier to HIV.
In Aim 2 C, we will test the product with the optimized combination of bioavailability enhancements and sustained release properties for protection against SHIV challenge in NHP.
A safe, effective HIV pre-exposure prophylaxis strategy with high levels of adherence is urgently needed to protect men and women at highest risk of HIV infection from anal sex. We propose development of a TFV enema to take advantage of common enema use associated with anal sex and the proven efficacy of TFV. This project optimizes the TFV enema formulation in animal models to inform clinical development.
|Pines, H A; Strathdee, S A; Hendrix, C W et al. (2018) Oral and vaginal HIV pre-exposure prophylaxis product attribute preferences among female sex workers in the Mexico-US border region. Int J STD AIDS :956462418793038|
|Pines, Heather A; Semple, Shirley J; Strathdee, Steffanie A et al. (2018) Vaginal washing and lubrication among female sex workers in the Mexico-US border region: implications for the development of vaginal PrEP for HIV prevention. BMC Public Health 18:1009|
|Figueroa, Dominique B; Madeen, Erin P; Tillotson, Joseph et al. (2018) Genetic Variation of the Kinases That Phosphorylate Tenofovir and Emtricitabine in Peripheral Blood Mononuclear Cells. AIDS Res Hum Retroviruses 34:421-429|
|Presnell, Aubrey L; Chuchuen, Oranat; Simons, Morgan G et al. (2018) Full depth measurement of tenofovir transport in rectal mucosa using confocal Raman spectroscopy and optical coherence tomography. Drug Deliv Transl Res 8:843-852|
|Carballo-Diéguez, Alex; Lentz, Cody; Giguere, Rebecca et al. (2018) Rectal Douching Associated with Receptive Anal Intercourse: A Literature Review. AIDS Behav 22:1288-1294|
|Hoang, Thuy; Date, Abhijit A; Ortiz, Jairo Ortiz et al. (2018) Development of rectal enema as microbicide (DREAM): Preclinical progressive selection of a tenofovir prodrug enema. Eur J Pharm Biopharm :|
|Hummert, Pamela; Parsons, Teresa L; Ensign, Laura M et al. (2018) Validation and implementation of liquid chromatographic-mass spectrometric (LC-MS) methods for the quantification of tenofovir prodrugs. J Pharm Biomed Anal 152:248-256|
|Carballo-Dieguez, Alex; Giguere, Rebecca; Lentz, Cody et al. (2018) Rectal Douching Practices Associated with Anal Intercourse: Implications for the Development of a Behaviorally Congruent HIV-Prevention Rectal Microbicide Douche. AIDS Behav :|
|Xiao, Peng; Gumber, Sanjeev; Marzinke, Mark A et al. (2018) Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection. Antimicrob Agents Chemother 62:|
|Aung, Wutyi S; Bakshi, Rahul P; Breakey, Jennifer et al. (2018) Fecal Coliform Bacterial Detection to Assess Enema Adherence in HIV Prevention Clinical Studies. AIDS Behav :|
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