Cellular pharmacology of tenofovir and emtricitabine for HIV prophylaxis

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DESCRIPTION (provided by applicant): 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.