Abstract
Rectal enemas that contain prophylactic levels of anti-HIV microbicides such as tenofovir have emerged as a promising dosage form to prevent sexually transmitted HIV infections. The enema vehicle is promising due to its likely ability to deliver a large amount of drug along the length of the rectal canal. Computational models of microbicide drug delivery by enemas can help their design process by determining key factors governing drug transport and, more specifically, the time history and degree of protection. They can also inform interpretations of experimental pharmacokinetic measures such as drug concentrations in biopsies. The present work begins rectal microbicide PK modeling, for enema vehicles. Results here show that a paramount factor in drug transport is the time of enema retention; direct connectivity between enema fluid and the fluid within rectal crypts is also important. Computations of the percentage of stromal volume protected by a single enema dose indicate that even with only a minute of enema retention, protection of 100% can be achieved after around 14 minutes post dose. Concentrations in biopsies are dependent on biopsy thickness; and control and/or knowledge of thickness could improve accuracy and decrease variability in biopsy measurements. Results here provide evidence that enemas are a promising dosage form for rectal microbicide delivery, and offer insights into their rational design.
Highlights
Acting microbicides are being developed as an important prophylactic modality in the fight against infection by sexually transmitted HIV[1,2,3]
The fundamental solutions to this model are the concentration distributions of tenofovir and tenofovir diphosphate as functions of position and time after enema application within the crypt fluid and local mucosal layers, and the volume average concentration in the blood
We have introduced a deterministic model to apply in helping understand the multiple factors that govern drug delivery to the rectal mucosa and its sampling by biopsies, with application to a leading microbicide drug, tenofovir, as delivered by an enema
Summary
Acting microbicides are being developed as an important prophylactic modality in the fight against infection by sexually transmitted HIV[1,2,3]. Different topical dosage forms have been proposed and are in various stages of development; these include gels, intravaginal rings, solid inserts and suppositories, and films[4,5,6,7,8]. Original microbicide development was for vaginal application, and was followed by rectal microbicide candidates[9]. Different microbicide product types have been intended for application to the vaginal vs rectal canals. Gels were the original dosage form, originally for the vagina and later for the rectum[10]. An enema vehicle has been proposed for rectal microbicide
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