N-甲基-d-天冬氨酸受体(NMDAR)介导的神经传递在认知和记忆中起关键作用,和d-丝氨酸是受体的共激动剂。d-丝氨酸被d-氨基酸氧化酶(DAAO)代谢。苯甲酸钠是一种DAAO抑制剂,可导致d-丝氨酸水平升高并增强NMDAR功能,可作为广谱中枢神经系统(CNS)疾病的治疗剂,包括精神分裂症和痴呆.苯甲酸钠在中枢神经系统疾病的治疗应用,我们进行了第一阶段的研究来评估它的安全性,耐受性,健康志愿者单剂量口服给药后的药代动力学特征。与中枢神经系统中的积累相反,在外周测量时,苯甲酸钠具有快速的药代动力学特征。
在这个第一阶段的研究中,受试者在单次口服给药后随机分为4个不同剂量组.在暴露于250、500、1000和2000mg苯甲酸钠后评估苯甲酸钠的药代动力学参数。调查并记录所有不良事件。
在禁食条件下,苯甲酸钠的Cmax和AUC在250至2000mg的剂量范围内表现出高于剂量比例的增加。Cmax和AUC的斜率分别为1.78和2.61,90%CI分别为1.41至2.15和2.20至3.03,分别。苯甲酸钠被迅速吸收并转化为苯甲酸,0.5小时后达到Cmax,0.3小时后消除t1/2。没有受试者报告与苯甲酸钠相关的不良事件。
在高达2000mg的剂量范围内观察到非线性药代动力学反应。苯甲酸钠治疗表现出良好的安全性,并且在所有剂量水平下都具有良好的耐受性。该研究结果为研究该药物后续临床开发的有效性和安全性奠定了基础。
TFDA-103607047。
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.
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.
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.
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.
TFDA-103607047.