Tenofovir (TNV) and emtricitabine (FTC) are generally safe, effective, and exhibit appealing pharmacokinetic properties, as the pharmacologically-active phosphorylated moieties exhibit a long half-life in mononuclear cells of HIV-infected patients. These favorable characteristics provide an impetus to evaluate TNV and FTC in a new clinical setting, pre-exposure HIV prophylaxis in HIVnegative persons (PreP). Several large phase-III clinical trials for PreP are currently underway. However, no studies have compared the cellular pharmacology of TNV/FTC in HIV-negative versus HIV-infected persons. Without this knowledge, it is impossible to make the most informed dose and dosing decisions for this new indication. This application proposes a planning period in preparation for a phase II clinical research study to define and compare the cellular pharmacology of TNV and FTC in HIV-seronegative versus HIV-seropositive adults. The two goals of the planning period are: To fully develop a comprehensive manual of operations for the conduct of the phase II study and to submit complete documentation to all necessary regulatory agencies. The overall hypothesis for clinical ? research study is that HIV-infection significantly influences the cellular pharmacology of TNV and ? FTC. To illustrate, intracellular TNV-phosphates, the focus of our studies, are 3-fold higher and persist ? for 3-fold longer in resting versus activated mononuclear cells in vitro. We propose that these in vitro ? findings are relevant to humans because HIV infection significantly elevates the activation-state of ? mononuclear cells and tissues in vivo. Our study will elucidate, according to HIV serostatus, the rate ? that intracellular TNV/FTC rise to steady-state (relevant for the onset of action) and the terminal ? elimination rate (relevant for missed doses, dosing interruptions, and potential window for resistance). ? We will also investigate the potential for TNV to inhibit purine nucleoside phosphorylase (PNP) in vivo. ? The rationale for this aim arises from an in vitro study which showed that TNV-monophosphate ? potently inhibited PNP-mediated didanosine (ddI) breakdown. It is not known, however, whether TNV ? causes a generalized PNP inhibition in vivo, which is a fundamental gap in basic knowledge. Indirect ? evidence makes a case that TNV does in fact cause a generalized PNP inhibition in vivo, as TNV is ? associated with unexpected T-lymphocytopenia and, in other studies, hypouricemia. Our study will ? quantify, for the first time, generalized PNP inhibition by TNV in vivo. If our overall hypothesis is ? correct, TNV-phosphates will be higher in the """"""""resting cell-state"""""""" of HIV negative persons and ? generalized PNP inhibition will be more pronounced in these persons compared with HIV-infected ? persons. The new information learned in this phase II study will directly address the most important ? and clinically relevant pharmacologic considerations applicable to the indication of PreP. ? ? ? ?
