Evaluation of the Effects of Therapeutic and Supratherapeutic Doses of Agomelatine on the QT/QTc Interval: A Phase I, Randomized, Double-blind, Placebo-controlled and Positive-controlled, Crossover Thorough QT/QTc Study Conducted in Healthy Volunteers

The effects of the antidepressant agomelatine up to a supratherapeutic dose (400 mg, single dose) on the QT corrected (QTc) interval were assessed in a randomized, double-blind, placebo-and positive-controlled, crossover thorough QT/QTc study in young healthy volunteers (29 males and 31 females). The primary criterion was the study of male or female population-derived QT-corrected interval (QTcP). The main analysis on the QTcP demonstrated that among the 10 postdose measurement times planned, the largest 1-sided 95% confidence interval upper bound of the difference between agomelatine 50 mg and placebo-adjusted means, and 1 of the differences between agomelatine 400 mg and placebo-adjusted means were both strictly inferior to the 10 millisecond upper-bound threshold of regulatory concern. The assay sensitivity was established with the positive control moxifloxacin (400 mg) and detected an effect on the mean QTcP interval that is around the threshold of regulatory concern (5 milliseconds). No relationship between QTcP and plasma concentrations of agomelatine was observed. In conclusion, agomelatine up to 400 mg has no effect on the QTc interval as demonstrated in the present regulatory thorough QT/QTc study.