Effects of Different Meal Compositions and Fasted State on the Oral Bioavailability of Etravirine

Study Objective . To determine the effects of various meal compositions and the fasted state on the pharmacokinetics of etravirine, a nonnucleoside reverse transcriptase inhibitor. Design . Phase I, open‐label, randomized, repeated single‐dose, three‐period crossover trial. Setting . Clinical pharmacology unit. Participants . 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. Measurements and Main 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 (AUC last ) 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. Conclusion . 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.