【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。更多还原

【Abstract】 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.更多还原