Mechanistic Assessment of HIV Growth in Tissue Explant Samples
Tenofovir is a nucleoside reverse-transcriptase inhibitor that is given to high-risk populations as a pre-exposure prophylaxis (PrEP) agent to prevent the sexual transmission of HIV. It is metabolized intracellularly to its active metabolite, tenofovir diphosphate. In the development of PrEP products, it is critical to define tissue- and plasma-specific prophylactic concentrations of both the parent drug and the active metabolite. Therefore, using drug concentrations in plasma and tissue following rectal administration of tenofovir vaginal gel, we have developed a population pharmacokinetic model to describe the relationship between tenofovir and tenofovir diphosphate in plasma, rectal tissue, and rectal cells. We have linked this relationship to infection suppression using data from an ex vivo explant assay to create a semi-mechanistic population pharmacokinetic-pharmacodynamic model that can be used to predict in vivo tenofovir concentrations that are necessary to prevent HIV.