Advertisement

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

  • Author Footnotes
    # These authors contributed equally to this work.
    Yen-Shan Lin
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Research and Development, SyneuRx International (Taiwan) Corporation, Taipei, Taiwan
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to this work.
    Wei-Chung Mao
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Tri-Service General Hospital, Taipei, Taiwan

    Cheng-Hsin General Hospital, Taipei, Taiwan
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to this work.
    Nai-Tzu Yao
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Research and Development, SyneuRx International (Taiwan) Corporation, Taipei, Taiwan
    Search for articles by this author
  • Guochuan Emil Tsai
    Correspondence
    Address correspondence to: Guochuan Emil Tsai, UCLA School of Medicine, Los Angeles, 16111 Plummer St, North Hills, CA, 91343.
    Affiliations
    Department of Research and Development, SyneuRx International (Taiwan) Corporation, Taipei, Taiwan

    UCLA School of Medicine, Los Angeles, California, USA
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to this work.
Published:September 11, 2022DOI:https://doi.org/10.1016/j.clinthera.2022.08.008

      Highlights

      • Sodium benzoate is a lead compound of the novel mechanism, inhibition of D-amino acid oxidase, which is a new generation therapy for schizophrenia
      • Sodium benzoate absorbed and converted to benzoic acid rapidly, reaching Cmax about 0.5 hour and the elimination half-life (T1/2) about 0.3 hour
      • Sodium benzoate was safe and well tolerated in the dose range of 250 mg to 2000 mg and showed higher than the dose proportional increase in Cmax and AUC
      • The study serves as a foundation for the clinical development of sodium benzoate

      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 ∼0.5 hour and elimination t1/2 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.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Andreasen NC
        • Carpenter WT
        • Kane JM
        • Lasser RA
        • Marder SR
        • Weinberger DR.
        Remission in schizophrenia: proposed criteria and rationale for consensus.
        American Journal of Psychiatry. 2005; 162: 441-449
        • Roh D
        • Chang JG
        • Yoon S
        • Kim CH.
        Antipsychotic prescribing patterns in first-episode schizophrenia: a five-year comparison.
        Clinical Psychopharmacology and Neuroscience. 2015; 13: 275-282
        • Venkatasubramanian G.
        Understanding schizophrenia as a disorder of consciousness: biological correlates and translational implications from quantum theory perspectives.
        Clinical Psychopharmacology and Neuroscience. 2015; 13: 36-47
        • Carlsson A.
        Antipsychotic drugs, neurotransmitters, and schizophrenia.
        American Journal of Psychiatry. 1978; 135: 164-173
        • Meltzer HY
        • Matsubara S
        • Lee JC.
        Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values.
        Journal of Pharmacology and Experimental Therapeutics. 1989; 251: 238
        • Nasrallah HA.
        The roles of efficacy, safety, and tolerability in antipsychotic effectiveness: practical implications of the CATIE schizophrenia trial.
        The Journal of Clinical Psychiatry. 2007; 68: 5-11
        • Moore T
        • Buchanan R
        • Buckley P
        • et al.
        The Texas Medication Algorithm Project Antipsychotic Algorithm for Schizophrenia: 2006 update.
        The Journal of Clinical Psychiatry. 2007; 68: 1751-1762
        • Lehman AF
        • Lieberman J
        • Dixon L
        • et al.
        Practice guideline for the treatment of patients with schizophrenia, second edition.
        American Journal of Psychiatry. 2004; 161: 1-56
        • Lieberman JA
        • Stroup TS
        • McEvoy JP
        • et al.
        Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.
        New England Journal of Medicine. 2005; 353: 1209-1223
        • Abbott A.
        Schizophrenia: the drug deadlock.
        Nature. 2010; 468: 158-159
        • Tsai G
        • Coyle JT.
        Glutamatergic mechanisms in schizophrenia.
        Annual Review of Pharmacology and Toxicology. 2002; 42: 165-179
        • Olney JW
        • Farber NB.
        Glutamate receptor dysfunction and schizophrenia.
        Archives of General Psychiatry. 1995; 52: 998-1007
        • Lin CH
        • Lane HY
        • Tsai GE.
        Glutamate signaling in the pathophysiology and therapy of schizophrenia.
        Pharmacology Biochemistry and Behavior. 2012; 100: 665-677
        • Krystal JH
        • Karper LP
        • Seibyl JP
        • et al.
        Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans: Psychotomimetic, Perceptual, Cognitive, and Neuroendocrine Responses.
        Archives of General Psychiatry. 1994; 51: 199-214
        • Noga JT
        • Hyde TM
        • Herman MM
        • et al.
        Glutamate receptors in the postmortem striatum of schizophrenic, suicide, and control brains.
        Synapse. 1997; 27 (doi.org/10.1002/(SICI)1098-2396(199711)27:3<168::AID-SYN2>3.0.CO;2-B): 168-176
        • Sokolov
        BP.Expression of NMDAR1, G1uR1, G1uR7, and KA1 Glutamate Receptor MRNAs Is Decreased in Frontal Cortex of “Neuroleptic-Free” Schizophrenics: Evidence on Reversible Up-Regulation by Typical Neuroleptics.
        J Neurochem. 1998; 71: 2454-2464
        • Javitt DC
        • Zukin SR.
        Recent advances in the phencyclidine model of schizophrenia.
        The American Journal of Psychiatry. 1991; 148: 1301-1308
        • Gordh T
        • Kristensen JD.
        The NMDA receptor antagonist CPP abolishes neurogenic “wind-up pain” after intrathecal administration in humans.
        Regional Anesthesia. 1992; 17: 82
        • Tsai G
        • Yang P
        • Chung LC
        • Lange N
        • Coyle JT.
        D-serine added to antipsychotics for the treatment of schizophrenia.
        Biological Psychiatry. 1998; 44: 1081-1089
        • Heresco-Levy U
        • Javitt DC
        • Ebstein R
        • et al.
        D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia.
        Biological Psychiatry. 2005; 57: 577-585
        • Scolari M
        • Acosta G.
        D-serine: a new word in the glutamatergic neuro-glial language.
        Amino Acids. 2007; 33: 563-574
        • Mattevi A
        • Vanoni MA
        • Todone F
        • et al.
        Crystal structure of D-amino acid oxidase: a case of active site mirror-image convergent evolution with flavocytochrome b2.
        Proceedings of the National Academy of Sciences of the United States of America. 1996; 93: 7496-7501
        • Madeira C
        • Freitas ME
        • Vargas-Lopes C
        • Wolosker H
        • Panizzutti R.
        Increased brain d-amino acid oxidase (DAAO) activity in schizophrenia.
        Schizophrenia Research. 2008; 101: 76-83
        • Verrall L
        • Burnet P
        • Betts J
        • Harrison P.
        The neurobiology of D-amino acid oxidase (DAO) and its involvement in schizophrenia.
        Molecular Psychiatry. 2009; 15: 122-137
        • Fukui K
        • Miyake Y.
        Molecular cloning and chromosomal localization of a human gene encoding D- amino-acid oxidase.
        The Journal of Biological Chemistry. 1992; 267: 18631-18638
        • Vanoni MA
        • Cosma A
        • Mazzeo D
        • Mattevi A
        • Todone F
        • Curti B.
        Limited proteolysis and X-ray crystallography reveal the origin of substrate specificity and of the rate-limiting product release during oxidation of d-amino acids catalyzed by mammalian d-amino acid oxidase.
        Biochemistry. 1997; 36: 5624-5632
        • Sasabe J
        • Miyoshi Y
        • Suzuki M
        • et al.
        D-amino acid oxidase controls motoneuron degeneration through D-serine.
        Proceedings of the National Academy of Sciences. 2012; 109: 627
        • Almond SL
        • Fradley RL
        • Armstrong EJ
        • et al.
        Behavioral and biochemical characterization of a mutant mouse strain lacking D-amino acid oxidase activity and its implications for schizophrenia.
        Molecular and Cellular Neurosciences. 2006; 32: 324-334
      1. Rais R, Thomas AG, Wozniak K, et al. Pharmacokinetics of oral D-serine in D-amino acid oxidase knockout mice. Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2012;40:2067-2073.

        • Coyle J
        • Tsai G.
        NMDA receptor function, neuroplasticity, and the pathophysiology of schizophrenia.
        International Review of Neurobiology. 2004; 59: 491-515
        • Chun-Da C
        • Wang J
        • Wang B
        • et al.
        Decreased levels of serum brain-derived neurotrophic factor in drug-naive first-episode schizophrenia: relationship to clinical phenotypes.
        Psychopharmacology. 2009; 207: 375-380
        • Lane HY
        • Lin CH
        • Green MF
        • et al.
        Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of d-amino acid oxidase inhibitor.
        JAMA Psychiatry. 2013; 70: 1267-1275
        • Lin CH
        • Lin CH
        • Chang YC
        • et al.
        Sodium benzoate, a D-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial.
        Biological Psychiatry. 2018; 84: 422-432
        • Bray HG
        • Thorpe WV
        • White K.
        Kinetic studies of the metabolism of foreign organic compounds; the formation of benzoic acid from benzamide toluene, benzyl alcohol and benzaldehyde and its conjugation with glycine and glucuronic acid in the rabbit.
        The Biochemical Journal. 1951; 48: 88-96
        • Quick AJ.
        On the chemistry of the conjugation of benzoic acid.
        Journal of Biological Chemistry. 1932; 95: 189-196
        • Kubota K
        • Ishizaki T.
        Dose-dependent pharmacokinetics of benzoic acid following oral administration of sodium benzoate to humans.
        European Journal of Clinical Pharmacology. 2004; 41: 363-368
        • Lane HY
        • Tu CH
        • Lin WC
        • Lin CH.
        Brain activity of benzoate, a D-amino acid oxidase inhibitor, in patients with mild cognitive impairment in a randomized, double-blind, placebo controlled clinical trial.
        International Journal of Neuropsychopharmacology. 2021; 24: 392-399
        • Lin CH
        • Chen PK
        • Wang SH
        • Lane HY.
        Sodium benzoate for the treatment of behavioral and psychological symptoms of dementia (BPSD): a randomized, double-blind, placebo-controlled, 6-week trial.
        Journal of Psychopharmacology. 2019; 33: 1030-1033
        • Lin CH
        • Chen PK
        • Chang YC
        • et al.
        Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial.
        Biological Psychiatry. 2013; : 75
        • Lin CH
        • Wang SH
        • Lane HY.
        Effects of sodium benzoate, a D-amino acid oxidase inhibitor, on perceived stress and cognitive function among patients with late-life depression: a randomized, double-blind, sertraline- and placebo-controlled trial.
        International Journal of Neuropsychopharmacology. 2022; 25: 545-555
        • Yang P.
        A Pilot trial of sodium benzoate, a D-amino acid oxidase inhibitor, added on augmentative and alternative communication intervention for non-communicative children with autism spectrum disorders.
        Translational Medicine. 2017; 6: 1-5
        • Batshaw ML
        • Hyman SL
        • Coyle JT
        • et al.
        Effect of sodium benzoate and sodium phenylacetate on brain serotonin turnover in the ornithine transcarbamylase-deficient sparse-fur mouse.
        Pediatric Research. 1988; 23: 368-374