Tenofovir, Emtricitabine Intracellular and Plasma, and Efavirenz Plasma Concentration Decay Following Drug Intake Cessation

Abstract

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. 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. 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. 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.