HIV pre-exposure prophylaxis: mucosal tissue drug distribution of RT inhibitor Tenofovir and entry inhibitor Maraviroc in a humanized mouse model

Abstract

Pre-exposure prophylaxis (PrEP) strategies utilizing anti-retroviral drugs show considerable promise for HIV prevention. However there is insufficient pharmacokinetic (PK) data on drug concentrations required for protection at the relevant mucosal tissues where the infection is initiated. Here we evaluated the utility of a humanized mouse model to derive PK data on two leading drugs, the RT inhibitor Tenofovir (TFV) and CCR5 inhibitor Maraviroc (MVC). Following oral dosing, both the drugs and the intracellular active TFV-diphosphate could be detected in vaginal, rectal and intestinal tissues. The drug exposures (AUC₂₄ h) were found to be higher in vaginal tissue compared to plasma with even higher levels detected in rectal and intestinal tissues. The overall trends of drug concentrations seen in humanized mice reflect those seen in the human thus establishing the utility of this model complementing the present non-human primate (NHP) models for future pre-clinical evaluations of promising HIV PrEP drug candidates.

Keywords: Anti-retroviral drug pharmacokinetics in humanized mice; HIV pre-exposure prophylaxis in hu-mice; Humanized mice for HIV PrEP PK studies; Tenofovir and maraviroc phamacokinetics in hu-mice.