P43.10
Background: Different vaginal dosing (BAT24, daily) of the 1% Tenofovir (TFV) gel gave differing pharmacokinetics and prophylactic efficacy. The kinetics of stromal Tenofovir diphosphate (TFV-DP) production/loss are governed by many factors, e.g.: mass transport kinetics of TFV to stroma; concentration distribution of stromal host cells; TFV binding and phosphorylation rates to/in host cells; and TFV-DP clearance rate in host cells. Experimental PK studies give guidance on creation and persistence of stromal TFV-DP levels, but optimization of dosing to achieve such levels is limited. Modeling this process complements experimental studies, providing insights on how the multiple factors govern TFV-DP levels and suggesting optimal dosing strategies.
Methods: A mechanistic, mass transport-based model was created of TFV delivery to human vaginal mucosa by a spreading gel, and coupled TFV-DP production in stromal host cells. Parameters in the model were obtained from in vitro measurements of gel rheology and TFV transport properties, human vaginal morphometric and histological data, and results of human PK studies for the 1% TFV gel. Single and multiple gel application regimens were studied, including coitus.
Results: Results show, for example, that application of two doses 4 hours apart (as found in BAT24) gives 40% higher maximum stromal TFV-DP concentration than daily dosing. This elevated TFV-DP concentration is sustained for 4 days vs daily dosing (due primarily to the long half life of TFV-DP).
Conclusions: Modeling provides additional insights about interactive effects of the multiple factors that govern optimal dosing by the TFV gel. Results here illustrate pharmacokinetic benefits of multiple dosing within a few hours vs sustained daily dosing. This approach can be used to help optimize dosage regimen, accounting for factors such as gel volume and drug loading.
