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

Autor: Lin YS; Department of Research and Development, SyneuRx International (Taiwan) Corporation, Taipei, Taiwan., Mao WC; Tri-Service General Hospital, Taipei, Taiwan; Cheng-Hsin General Hospital, Taipei, Taiwan., Yao NT; Department of Research and Development, SyneuRx International (Taiwan) Corporation, Taipei, Taiwan., Tsai GE; Department of Research and Development, SyneuRx International (Taiwan) Corporation, Taipei, Taiwan; UCLA School of Medicine, Los Angeles, California, USA. Electronic address: tsaimdphd@ucla.edu.
Jazyk: angličtina
Zdroj: Clinical therapeutics [Clin Ther] 2022 Oct; Vol. 44 (10), pp. 1326-1335. Date of Electronic Publication: 2022 Sep 11.
DOI: 10.1016/j.clinthera.2022.08.008
Abstrakt: 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.
Competing Interests: Declarations of Interest Drs. Tsai, Lin, and Yao are affiliated with SyneuRx International (Taiwan) Corp. Dr. Mao is a current emplyee of Tri-Service General Hospital. This study was executed and the data analyzed by Rosetta Pharmamate Co, Ltd.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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