Dose-Proportionality and Intra-Individual Variability of Intracellular TFV-DP and FTC-TP in Healthy Volunteers

This PK study is designed to establish the dose-proportionality of TFV and FTC (serum and
intracellular forms) with daily to weekly dosing. This information is essential to (1)
employ drug concentration as an adherence measure in future PrEP studies, and (2) to
estimate the anticipated concentration of parent and active moieties of TFV and FTC in
intermittent PrEP regimens associated with full adherence to a prescribed regimen. In
addition, intra-individual variability will be assessed to improve sample size estimates in
future PrEP studies that use drug concentration as an adherence measure or where PK-PD
correlations are planned. The dose-proportionality of intra-cellular phosphates of the two
components of the study product has not previously been established. Given the complexity of
movement of these drugs between body compartments (central compartment, vaginal mucosal
tissue, vaginal lumen, gastrointestinal mucosal tissue, gastrointestinal lumen), into cells
within these compartments, and intra-cellular phosphorylation, it is possible that non-dose
proportional kinetics, such as mixed or zero-order saturable processes may be operating.