Effects of different meal compositions and fasted state on the oral bioavailability of etravirine.
OBJECTIVE
To determine the effects of various meal compositions and the fasted state on the pharmacokinetics of etravirine, a nonnucleoside reverse transcriptase inhibitor.


METHODS
Phase I, open-label, randomized, repeated single-dose, three-period crossover trial.


METHODS
Clinical pharmacology unit.


METHODS
Two parallel panels of 12 human immunodeficiency virus (HIV)-negative, healthy, male volunteers. Twenty volunteers completed the study; three withdrew consent, and one was lost to follow-up. Intervention. Panel 1 received a single dose of etravirine 100 mg after a standard breakfast, in the fasted state, and after a light breakfast (croissant). Panel 2 received the same treatment after a standard breakfast, after an enhanced-fiber breakfast, and after a high-fat breakfast. Each treatment was separated by a washout period of at least 14 days.


RESULTS
For each treatment, full pharmacokinetic profiles of etravirine were determined up to 96 hours after dosing. Pharmacokinetic parameters were determined by noncompartmental methods and analyzed using a linear mixed-effects model for a crossover design. The least-squares mean ratio for the area under the plasma concentration-time curve from time of administration to the last time point with a measurable concentration after dosing (AUClast) was 0.49 (90% confidence interval [CI] 0.39-0.61) for the fasted state compared with dosing after a standard breakfast. When dosing occurred after a light or enhanced-fiber breakfast, the corresponding values were 0.80 (90% CI 0.69-0.94) and 0.75 (90% CI 0.63-0.90), respectively. When administered after a high-fat breakfast the least-squares mean ratio of AUC(last) was 1.09 (0.84-1.41), compared with dosing after a standard breakfast. Adverse events were also assessed. Under all conditions, single doses of etravirine 100 mg were generally safe and well tolerated.


CONCLUSIONS
Administration of etravirine in a fasted state resulted in 51% lower mean exposure compared with dosing after a standard breakfast. Etravirine should be administered following a meal to improve bioavailability; however, differences in exposure after a standard breakfast versus a high-fat, enhanced-fiber, or light breakfast (croissant) were not considered clinically relevant.
Schöller-Gyüre
Monika
M
Tibotec BVBA, Mechelen, Belgium.
Boffito
Marta
M
Pozniak
Anton L
AL
Leemans
Ruud
R
Kakuda
Thomas N
TN
Woodfall
Brian
B
Vyncke
Veerle
V
Peeters
Monika
M
Vandermeulen
Kati
K
Hoetelmans
Richard M W
RM
D000284:Administration, Oral; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D005215:Fasting; D005502:Food; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011724:Pyridazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine