Pharmacokinetics and Safety of Sodium Benzoate, a d-Amino Acid Oxidase (DAAO) Inhibitor, in Healthy Subjects: A Phase I, Open-label Study

Yen-Shan Lin; Wei-Chung Mao; Nai-Tzu Yao; Guochuan Emil Tsai

doi:10.1016/j.clinthera.2022.08.008

Pharmacokinetics and Safety of Sodium Benzoate, a d-Amino Acid Oxidase (DAAO) Inhibitor, in Healthy Subjects: A Phase I, Open-label Study

Clin Ther. 2022 Oct;44(10):1326-1335. doi: 10.1016/j.clinthera.2022.08.008. Epub 2022 Sep 11.

Authors

Yen-Shan Lin¹, Wei-Chung Mao², Nai-Tzu Yao¹, Guochuan Emil Tsai³

Affiliations

¹ Department of Research and Development, SyneuRx International (Taiwan) Corporation, Taipei, Taiwan.
² Tri-Service General Hospital, Taipei, Taiwan; Cheng-Hsin General Hospital, Taipei, Taiwan.
³ Department of Research and Development, SyneuRx International (Taiwan) Corporation, Taipei, Taiwan; UCLA School of Medicine, Los Angeles, California, USA. Electronic address: tsaimdphd@ucla.edu.

PMID: 36104267
DOI: 10.1016/j.clinthera.2022.08.008

Abstract

Purpose: N-methyl-d-aspartate receptor (NMDAR)-mediated neurotransmission plays a critical role in cognition and memory, and d-serine is a co-agonist of the receptor. d-serine is metabolized by d-amino acid oxidase (DAAO). Sodium benzoate is a DAAO inhibitor that leads to the elevation of d-serine levels and enhances NMDAR functions as a therapeutic for wide-spectrum central nervous system (CNS) disorders, including schizophrenia and dementia. For therapeutic application of sodium benzoate in CNS disorders, we conducted a Phase I study to evaluate its safety, tolerability, and pharmacokinetic profile after single-dose oral administration in healthy volunteers. In contrast to the accumulation in the CNS, sodium benzoate has a rapid pharmacokinetic profile when measured peripherally.

Methods: In this Phase I study, subjects were randomized into 4 different dose groups after a single oral administration. The pharmacokinetic parameters of sodium benzoate were assessed after exposure to 250, 500, 1000, and 2000 mg of sodium benzoate. All adverse events were investigated and recorded.

Findings: The C_max and AUC of sodium benzoate exhibited a higher than dose-proportional increase within the dose range from 250 to 2000 mg under fasting conditions. The slopes were 1.78 and 2.61 and the 90% CIs were 1.41 to 2.15 and 2.20 to 3.03 for C_max and AUC, respectively. Sodium benzoate was absorbed and converted to benzoic acid rapidly, reaching C_max after ∼0.5 hour and elimination t_1/2 after ∼0.3 hour. No subjects reported adverse events that were sodium benzoate related.

Implications: The nonlinear pharmacokinetic response was observed within the dose range up to 2000 mg. Sodium benzoate treatment exhibited a favorable safety profile and was well tolerated at all dose levels. The study results serve as a foundation that should be useful for investigating efficacy and safety in the drug's subsequent clinical development.

Trial registration: TFDA-103607047.

Keywords: NMDA; d-amino acid oxidase; pharmacokinetics; safety; schizophrenia; sodium benzoate.

Publication types

Randomized Controlled Trial
Clinical Trial, Phase I
Research Support, Non-U.S. Gov't

MeSH terms

Area Under Curve
Double-Blind Method
Healthy Volunteers
Humans
Oxidoreductases* / metabolism
Serine / metabolism
Sodium Benzoate* / adverse effects

Substances

Sodium Benzoate
Oxidoreductases
Serine