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

BACKGROUND: 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.

PURPOSE: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: Ammoxetine has a favorable pharmacokinetic profile after oral administration and good safety properties. The PK and safety profiles of ammoxetine could enable further clinical development in patients with major depressive disorder.