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 Cmax 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 Cmax and AUC, respectively. Sodium benzoate was absorbed and converted to benzoic acid rapidly, reaching Cmax after â¼0.5 hour and elimination t1/2 after â¼0.3 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.
