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

Qi Shen, Chao Hu, Jia Miao, Junxia Chen, Yueying Peng, Tingting Pan, Xiaolin He, Jing Yuan, Shaonan Ni, Yongsheng Wang, Zhu Luo
European Journal of Pharmaceutical Sciences 2021 January 19, : 105724

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.

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