Development of rectal enema as microbicide (DREAM): Preclinical progressive selection of a tenofovir prodrug enema

Thuy Hoang, Abhijit A. Date, Jairo Ortiz Ortiz, Ting Wei Young, Sabrine Bensouda, Peng Xiao, Mark A Marzinke, Lisa Rohan, Edward Fuchs, Craig Hendrix, Sanjeev Gumber, Francois Villinger, Richard A. Cone, Justin S Hanes, Laura Ensign-Hodges

Research output: Contribution to journalArticle

Abstract

HIV pre-exposure prophylaxis (PrEP) strategies have the potential to prevent millions of incident HIV infections each year. However, the efficacy of PrEP strategies has been plagued by issues of non-adherence, likely because of the difficulty in motivating otherwise healthy people to adhere to treatment regimens that require significant behavioral changes and daily discipline. An alternative approach to PrEP is to focus on strategies that fit in to normal, and even desirable, sexual behaviors, such as the use of cleansing enemas by men who have sex with men (MSM) prior to receptive anal intercourse (RAI). Here, we describe preclinical efforts toward optimizing a tenofovir (TFV)-based enema formulation for rectal PrEP. Using a murine model, we compared the plasma and tissue pharmacokinetics of TFV and various TFV prodrugs, including tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and hexadecyloxypropyl tenofovir (CMX157), after dosing as enema formulations with varying osmolality and ion content. We observed that the enema vehicle composition played a more important role than the TFV prodrug properties in achieving rapid and therapeutically relevant tenofovir diphosphate (TFV-DP) concentrations in mouse colorectal tissue. Our results support the next steps, which are further preclinical (non-human primate) and clinical development of a hypo-osmolar TFV enema product for rectal PrEP.

Original languageEnglish (US)
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • Fleet
  • Hypotonic
  • Rectal douche
  • Rectal gel
  • Sodium bicarbonate

ASJC Scopus subject areas

  • Biotechnology
  • Pharmaceutical Science

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