Pharmacokinetics and safety of etravirine administered once or twice daily after 2 weeks treatment with efavirenz in healthy volunteers.
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.
Boffito
Marta
M
Department of HIV/GUM Medicine, St. Stephen's Centre, Chelsea and Westminster Hospital, London, United Kingdom. marta.boffito@chelwest.nhs.uk
Jackson
Akil
A
Lamorde
Mohammed
M
Back
David
D
Watson
Victoria
V
Taylor
Jessica
J
Waters
Laura
L
Asboe
David
D
Gazzard
Brian
B
Pozniak
Anton
A
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
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; C098320:efavirenz