Dataset Information

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

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.

SUBMITTER: Hoang T

PROVIDER: S-EPMC6428633 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Hoang Thuy T Date Abhijit A AA Ortiz Jairo Ortiz JO Young Ting-Wei TW Bensouda Sabrine S Xiao Peng P Marzinke Mark M Rohan Lisa L Fuchs Edward J EJ Hendrix Craig C Gumber Sanjeev S Villinger Francois F Cone Richard A RA Hanes Justin J Ensign Laura M LM

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 20180524

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, s ...[more]

PMID: 29802984

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Project description:Gels are one of the soft material platforms being evaluated to deliver topically acting anti-HIV drugs (microbicides) to the vaginal environment. For each drug, its loaded concentration, gel properties and applied volume, and frequency of dosing can be designed to optimize PK and, thence, PD. These factors also impact user sensory perceptions and acceptability. Deterministic compartmental modeling of vaginal deployment and drug delivery achieved by test gels can help delineate how multiple parameters characterizing drug, vehicle, vaginal environment, and dosing govern details of PK and PD and also gel leakage from the canal. Such microbicide delivery is a transport process combining convection, e.g., from gel spreading along the vaginal canal, with drug diffusion in multiple compartments, including gel, mucosal epithelium, and stroma. The present work builds upon prior models of gel coating flows and drug diffusion (without convection) in the vaginal environment. It combines and extends these initial approaches in several key ways, including: (1) linking convective drug transport due to gel spreading with drug diffusion and (2) accounting for natural variations in dimensions of the canal and the site of gel placement therein. Results are obtained for a leading microbicide drug, tenofovir, delivered by three prototype microbicide gels, with a range of rheological properties. The model includes phosphorylation of tenofovir to tenofovir diphosphate (which manifests reverse transcriptase activity in host cells), the stromal concentration distributions of which are related to reference prophylactic values against HIV. This yields a computed summary measure related to gel protection ("percent protected"). Analyses illustrate tradeoffs amongst gel properties, drug loading, volume and site of placement, and vaginal dimensions, in the time and space history of gel distribution and tenofovir transport to sites of its anti-HIV action and concentrations and potential prophylactic actions of tenofovir diphosphate therein.

Dataset Information

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

Publications

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

Similar Datasets

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