Multi-Compartmental Transport of Anti-HIV Molecules into and through Mucosa

Abstract

Sexual transmission of HIV derives from contact of virions with host cells, e.g. in the epithelium and lamina propria of the vagina. Current antiviral drugs (e.g. the reverse transcriptase inhibitor Tenofovir) show promise for topical mucosal prophylactic action against transmission (termed “microbicides”). They can be introduced by multiple delivery systems, e.g. gels and intravaginal rings. Their success (pharmacodynamics) depends upon adequate distribution in time and space (pharmacokinetics) vs. distribution of invading virions. We have created a family of mechanistic transport models of microbicide molecules, as they distribute from different vehicles into and through vaginal fluids and mucosal tissues, and interact with host cells and virions. We report here two new models that characterize transport of antiviral molecules from a vaginal gel or ring into and through the vaginal epithelium and lamina propria, with uptake within the latter into blood capillaries. The models contain systems of coupled convection-diffusion equations - one for each compartment. These are solved numerically (MatLab and Comsol for gels and rings, respectively). We have applied these models to transport of Tenofovir, and compared results with in vivo measurements of drug levels (vaginal fluid, tissue, bloodstream) in two human studies of a 1% Tenofovir gel (CONRAD; MTN-001). The models show good agreement in predicting the drop in Tenofovir concentrations (vaginal fluids; biopsy) during 24h after a single application of 4 mL of gel (CONRAD), and also the quasi-steady state values in vaginal tissue biopsies, obtained during continuous once-per-day application of 4 mL of gel (MTN-001). We illustrate use of the models to understand tradeoffs amongst the packaging of drug in delivery vehicles with different properties and volumes/geometries, in relation to the frequency of application needed to create and sustain prophylactic drug levels in target mucosal compartments (NIH U19 AI077289).