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 Marzinke; Lisa Rohan; Edward J Fuchs; Craig Hendrix; Sanjeev Gumber; Francois Villinger; Richard A Cone; Justin Hanes; Laura M Ensign

doi:10.1016/j.ejpb.2018.05.030

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

Eur J Pharm Biopharm. 2019 May:138:23-29. doi: 10.1016/j.ejpb.2018.05.030. Epub 2018 May 24.

Authors

Affiliations

¹ The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA.
² The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA.
³ The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; Department of Medicine, Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, USA.
⁵ Department of Medicine, Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Pharmaceutical Sciences, University of Pittsburgh and Magee-Womens Research Institute, Pittsburgh, PA, USA.
⁷ Department of Medicine, Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA; Department of Medicine, Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
¹⁰ The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; Department of Biophysics, Johns Hopkins University, Baltimore, MD, USA.
¹¹ The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA. Electronic address: [email protected].
¹² The Center for Nanomedicine at the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA. Electronic address: [email protected].

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.

Keywords: Fleet; Hypotonic; Rectal douche; Rectal gel; Sodium bicarbonate.

MeSH terms

Adenine / analogs & derivatives
Adenine / pharmacology
Administration, Rectal
Alanine
Animals
Anti-HIV Agents / pharmacology
Anti-Infective Agents / pharmacology*
Enema / methods
HIV Infections / drug therapy
HIV-1 / drug effects
Homosexuality, Male
Male
Mice
Organophosphates / pharmacology
Organophosphonates / pharmacology
Pre-Exposure Prophylaxis / methods
Prodrugs / pharmacology*
Rectum / drug effects*
Sexual and Gender Minorities
Tenofovir / pharmacology*

Substances

Anti-HIV Agents
Anti-Infective Agents
Organophosphates
Organophosphonates
Prodrugs
tenofovir diphosphate
Tenofovir
tenofovir alafenamide
Adenine
hexadecyloxypropyl 9-(2-(phosphonomethoxy)propyl)adenine
Alanine

Abstract

MeSH terms

Substances

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