评估中国健康受试者在不同进食条件下口服DP-VPA片剂后的药动学和安全性  

Effect of Food on the Pharmacokinetics and Safety of DP-VPA and Its Metabolites in Healthy Chinese Subjects

作　　者：詹惠中 李熠 范亚新 陈渊成[3] 郁继诚[3] 郭蓓宁 刘笑芬 虞培敏 洪震 曹国英[1] 张菁[3] ZHAN Hui-zhong;LI Yi;FAN Ya-xin;CHEN Yuan-cheng;YU Ji-cheng;GUO Bei-ning;LIU Xiao-fen;YU Pei-ming;HONG Zhen;CAO Guo-ying;ZHANG Jing(GCP Office,Huashan Hospital,Fudan University,Shanghai 200040,China;Institute of Antibiotics,Huashan Hospital,Fudan University,Shanghai 200040,China;Clinical Pharmacological Research Center,Huashan Hospital,Fudan University,Shanghai 200040,China;Department of Neurology,Huashan Hospital,Fudan University,Shanghai 200040,China)

机构地区：[1]复旦大学附属华山医院药物临床试验机构办公室,上海200040 [2]复旦大学附属华山医院抗生素研究所,上海200040 [3]复旦大学附属华山医院临床药理研究中心,上海200040 [4]复旦大学附属华山医院神经科,上海200040

出　　处：《中国临床神经科学》2025年第1期57-64,共8页Chinese Journal of Clinical Neurosciences

基　　金：上海申康医院发展中心-促进市级医院临床技能与临床创新三年行动计划研究型医师创新转化能力培训项目(编号:SHDC2022CRS042)。

摘　　要：目的评估中国健康受试者在不同进食条件下口服丙戊酸(VPA)的磷脂前体药物DP-VPA后的药动学和安全性。方法采用随机、开放、3周期、3交叉、自身对照研究设计方法,选取12例健康受试者分别在空腹状态、进食普通餐或高脂餐后口服DP-VPA片剂900 mg。采用液质联用法测定血浆中DP-VPA的两个主要成分及其活性代谢产物浓度。以非房室模型法计算药动学参数,以峰浓度(c_(max))和药时曲线下面积(AUC)评估不同进食物条件下口服DP-VPA的药动学参数的影响,并监测整个研究过程中的不良事件。结果相较于空腹,普通餐和高脂餐组VPA的c_(max)、AUC_(0-120 h)以及半衰期(t_(1/2))等药动学参数均未见显著变化;棕榈酰丙戊酰磷脂(C16 DP-VPA)的c_(max)和AUC_(0-120 h)增加约1.5倍、t_(max)延长;硬脂酰丙戊酰磷脂(C18 DP-VPA)的c_(max)和AUC_(0-120 h)分别增加了1.787~2.788倍、t_(1/2)延长。药物相关不良事件主要为轻度头晕,呈一过性,未经处理自行恢复。结论在不同进食条件下活性代谢物VPA的药动学参数未见显著变化,高脂餐下DP-VPA的暴露量显著增加;3种不同进食条件下受试者安全性良好;推荐临床在空腹或进普通餐条件下口服DP-VPA片剂。Aim To assess the pharmacokinetics(PK)and safety of oral DP-VPA tablets under the different dietary conditions in healthy subjects in order to provide a reference for the clinical usage and dosage of this drug.Methods This randomized,open-label,three-cycle,triple-crossover,self-controlled study was used,included 12 healthy Chinese subjects who were given 900 mg of oral DP-VPA tablets under fasting conditions and after an ordinary diet or high-fat diet.The human plasma concentrations of the two active ingredients and its active metabolite were measured using liquid chromatography-mass spectrometry(LC-MS).The PK parameters were calculated using non-compartmental analysis.Peak concentration(c_(max))and area under concentration-time curve(AUC)were employed to assess the effect of different dietary conditions on the PK parameters.Adverse events were monitored throughout the study.Results After a single oral administration of DP-VPA tablet in healthy Chinese subjects under fasting conditions or after an ordinary diet or high-fat diet,compared with the fasted group,the ordinary diet and high-fat diet groups had no significant changes in the PK parameters of VPA such as c_(max),AUC_(0-120 h)and t_(1/2) of VPA.However,the c_(max),and AUC_(0-120 h)of C16 DP-VPA were increased by about 1.5 times and t_(max) was prolonged.Similarly,the c_(max),and AUC_(0-120 h)of C18 DP-VPA were increased by 1.787-2.788 times and t_(1/2) was prolonged.The drug-related adverse events were mainly transient mild dizziness and resolved without treatment.Conclusion Oral administration of DP-VPA tablet in healthy Chinese subjects under different dietary conditions exerts no effect on the PK or the in vivo exposure of its active metabolite VPA.However,DP-VPA exposure is significantly increased under high-fat diet.The drug exhibits good safety profile in the subjects under all three dietary conditions.Oral administration of DP-VPA under fasting conditions or after an ordinary diet is clinically recommended.

关 键 词：棕榈酰丙戊酰磷脂 硬脂酰丙戊酰磷脂 丙戊酸 食物影响 药动学 安全性 

分 类 号：R742.1[医药卫生—神经病学与精神病学]