Tenofovir, emtricitabine intracellular and plasma, and efavirenz plasma concentration decay following drug intake cessation: implications for HIV treatment and prevention.

Background: In vivo data on tenofovir (TFV), emtricitabine (FTC), and efavirenz (EFV) concentration decay after intake cessation are limited; determinations of "true" elimination half-lives (t½) have often been based on suboptimal sampling windows. Understanding these parameters is important in managing missed doses and planning HIV pre-exposure prophylaxis (PrEP). This study investigated the pharmacokinetics (PK) of plasma TFV/FTC, their intracellular (IC) anabolites, TFV-diphosphate (DP) and FTC-triphosphate (TP), and plasma EFV over 10 days after intake cessation in HIV-negative volunteers.

Methods: Volunteers received an Atripla (TFV/FTV/EFV) tablet daily for 14 days. PK sampling occurred before final dose and up to 228 hours after stopping. Peripheral blood mononuclear cells for [IC](drug) and [plasma](drug) were isolated, with analysis by tandem mass spectrometry.

Results: Sixteen participants completed the study. Geometric mean plasma (t½)(228h) of TFV and FTC were 31 and 37 hours. These were longer than the previous reports (TFV 12-18 hours, FTC 10 hours).Geometric mean (t½)(228h) of IC TFV-DP and FTC-TP were 164 and 39 hours, whereas for EFV in plasma was 92 hours. [EFV](plasma) in 5/16 participants were below the suggested MEC of 1000 ng/mL within 48 hours postdose; however, 50% of the participants maintained concentrations above this level after 84 hours.

Conclusions: These data fully characterize the PK of TFV and TFV-DP, FTC and FTC-TP, and EFV after stopping the drug combination. Although decay in concentrations can be related to a target for EFV, this is more difficult for the IC phosphates. Consensus on 'target' triphosphate/diphosphate concentrations will further our understanding of missed/delayed doses in treatment and prevention strategies.