First-in-human safety, tolerability, and pharmacokinetics of ammoxetine in healthy subjects: a randomized, double-blind, placebo-controlled phase I study

•What is already known about this subject•Ammoxetine is a novel selective serotonin and norepinephrine reuptake inhibitor with potential utility for therapy in major depressive disorder.•Pre-clinical studies in animal depression models indicated ammoxetine produces potent inhibition of 5-HT and NE reuptake and results in a robust antidepressant activity.•What this study adds•This first-in-human study provided the initial safety, tolerability and pharmacokinetic profiles of ammoxetine in healthy subjects.•The study investigated the effect of CYP2C19 polymorphisms on the metabolism of ammoxetine.•The favorable safety, tolerability and the linear pharmacokinetic profile of ammoxetine were observed, which could enable dose selections and further clinical development in subsequent studies in patients with major depressive disorder. : Ammoxetine is a novel selective serotonin and norepinephrine reuptake inhibitor. Preclinical studies have indicated the potential utility of ammoxetine for therapy in major depressive disorder. : To investigate the first-in-human safety, tolerability, and pharmacokinetics (PK) of ammoxetine in healthy subjects and evaluate the effect of CYP2C19 polymorphisms on metabolism of ammoxetine. : In this randomized, double-blind, placebo-controlled phase I study, healthy Chinese subjects were allocated to receive 2.5, 7.5, 15, 30, 45, 65, 100 mg ammoxetine or placebo in single-dose part and 15, 30, 45 mg ammoxetine or placebo twice daily for 8 days in multiple-dose part. Pharmacokinetic, safety and tolerability assessments were performed. : A total of 134 subjects were screened and 94 were enrolled. All the ammoxetine-related adverse events (AEs) were mild and resolved spontaneously. No hepatic AEs were reported during the study. Ammoxetine was well absorbed after oral administration with Tmax reached in 5.0-6.0 h. After single-dosing, Cmax and AUC increased proportionally with dose, except at 65 mg. After multiple-dosing, the exposures of ammoxetine at steady state increased slightly in a more-than-dose-proportional manner over the dose range studied, probably due to the saturated elimination. Steady state was achieved 6 days after multiple-dosing was initiated. The low extent of urinary excretion of ammoxetine (< 2%) indicated it is undergoing extensive metabolism. CYP2C19 polymorphisms had minimal effect on metabolism of ammoxetine. : Ammoxetine has a favorable pharmacokinetic profile after oral administration and good safety properties