title: Tenofovir, emtricitabine intracellular and plasma, and efavirenz plasma concentration decay following drug intake cessation: implications for HIV treatment and prevention.
abstract: 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.
authors.affiliation: SSAT, St. Stephen's Centre, Chelsea & Westminster Hospital, London, United Kingdom. akil.jackson@chelwest.nhs.uk
authors.forename: Akil
authors.initials: A
authors.lastname: Jackson
authors.forename: Graeme
authors.initials: G
authors.lastname: Moyle
authors.forename: Victoria
authors.initials: V
authors.lastname: Watson
authors.forename: John
authors.initials: J
authors.lastname: Tjia
authors.forename: Alieu
authors.initials: A
authors.lastname: Ammara
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.forename: Malika
authors.initials: M
authors.lastname: Mohabeer
authors.forename: Brian
authors.initials: B
authors.lastname: Gazzard
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004338:Drug Combinations; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000517:prevention & control; D006207:Half-Life; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D000068698:Tenofovir; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004338:Drug Combinations; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C098320:efavirenz