title: Pharmacokinetics and safety of etravirine administered once or twice daily after 2 weeks treatment with efavirenz in healthy volunteers.
abstract: OBJECTIVE
  To assess the pharmacokinetics of etravirine once and twice daily without and with a preceding efavirenz intake period in healthy volunteers.
  
  
  METHODS
  Volunteers were randomized to receive etravirine 400 mg once daily (arm 1) or 200 mg twice daily (arm 2) for 14 days. All subjects underwent a washout period of 14 days and then took efavirenz 600 mg once daily for 14 days. Arm 1 and 2 restarted etravirine once and twice daily for 14 days. Etravirine pharmacokinetics was assessed for each phase (before and after efavirenz 14-day intake) on days 1 and 14. Efavirenz concentrations were measured daily for 14 days after intake withholding. Pharmacokinetic parameters were compared (before and after efavirenz 14-day intake) by determining geometric mean ratios and 90% confidence intervals.
  
  
  RESULTS
  Twenty-five subjects (9 female) completed the study. Steady-state etravirine pharmacokinetic parameters were significantly lower after efavirenz intake in the once-daily and twice-daily arms: geometric mean ratios and 90% confidence intervals were 0.71 (0.62 to 0.81) for AUC 0-24, 0.78 (0.70 to 0.86) for Cmax, 0.67 (0.49 to 0.91) for Ctrough for once daily; and 0.72 (0.63 to 0.81) for AUC 0-12, 0.79 (0.70 to 0.90) for Cmax, and 0.63 (0.54 to 0.73) for Ctrough for twice daily. All subjects had detectable efavirenz concentrations 7 days after stopping efavirenz intake, 5 above the suggested minimum effective concentration of 1000 ng/mL.
  
  
  CONCLUSIONS
  The induction effect of efavirenz persists for at least 2 weeks after stopping drug intake. The decrease in etravirine is not considered clinically significant. Further clinical data are warranted.
authors.affiliation: Department of HIV/GUM Medicine, St. Stephen's Centre, Chelsea and Westminster Hospital, London, United Kingdom. marta.boffito@chelwest.nhs.uk
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
authors.forename: Akil
authors.initials: A
authors.lastname: Jackson
authors.forename: Mohammed
authors.initials: M
authors.lastname: Lamorde
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.forename: Victoria
authors.initials: V
authors.lastname: Watson
authors.forename: Jessica
authors.initials: J
authors.lastname: Taylor
authors.forename: Laura
authors.initials: L
authors.lastname: Waters
authors.forename: David
authors.initials: D
authors.lastname: Asboe
authors.forename: Brian
authors.initials: B
authors.lastname: Gazzard
authors.forename: Anton
authors.initials: A
authors.lastname: Pozniak
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010949:Plasma / Q000737:chemistry; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; C098320:efavirenz