索磷布韦片在中国健康人体中生物等效性和安全性评价  

Bioequivalence and safety of sofosbuvir tablets in the healthy Chinese subjects

作　　者：刘广文[1] 高振月 于爽 薛金玲 梁文忠 兰静 杨海淼[1] LIU Guangwen;GAO Zhenyue;YU Shuang;XUE Jinling;LIANG Wenzhong;LAN Jing;YANG Haimiao(Phase I Clinical Trial Laboratory,The Affiliated Hospital of Changchun University of Chinese Medicine,Changchun 130021,China;Chia Tai Tianqing Pharmaceutical Group Co.,Ltd.,Nanjing 210000,China;Shanghai WuXi AppTec New Drug Development Co.,Ltd.,Shanghai 215000,China)

机构地区：[1]长春中医药大学附属医院Ⅰ期临床试验研究室,长春130021 [2]正大天晴药业集团股份有限公司,南京210000 [3]上海药明康德新药开发有限公司,上海215000

出　　处：《临床肝胆病杂志》2020年第12期2688-2694,共7页Journal of Clinical Hepatology

摘　　要：目的研究索磷布韦片药代动力学特征,对2种制剂的生物等效性和安全性进行评价。方法健康受试志愿者均通过长春中医药大学附属医院临床试验招募报名平台征集,空腹组和餐后组分别在2018年9月18日和9月28日集中进行受试者的筛选体检,体检结果符合纳入标准后入组。空腹组和餐后组各40例健康受试者分别口服索磷布韦片受试试剂和参比试剂索磷布韦片索华迪(SOVALDI,400 mg),本研究为随机、开放、两序列、四周期、单次给药、完全重复交叉健康人体空腹及餐后状态下生物等效性试验,其中空腹组口服受试试剂和参比试剂各20例,餐后组口服受试试剂和参比试剂各20例。液相串联质谱测定人EDTA-K2血浆中索磷布韦及其主要代谢物GS-331007的含量,检测索磷布韦0 h至服药后8 h共计15个时间点血药浓度;检测GS-331007为0 h至服药后72 h共计16个时间点的血药浓度,采用WinNonlin软件计算药代动力学参数,并进行生物等效性评价。结果受试者空腹状态下口服受试制剂和参比制剂后,以索磷布韦的主要药代动力学参数评价受试制剂与参比制剂的生物等效性,Cmax、AUC0-t、AUC0-inf的几何均值比值分别为90.55%、97.26%、94.62%;以GS-331007的主要药代动力学参数评价受试制剂与参比制剂的生物等效性,Cmax、AUC0-t、AUC0-inf的几何均值比值分别为98.91%、98.98%、99.46%,均在80.00%~125.00%。对索磷布韦的药代动力学参数Cmax、AUC0-t、AUC0-inf经自然对数转换后,进行方差分析,结果显示序列、周期、制剂对Cmax、AUC0-t、AUC0-inf均无显著影响(P值均>0.05)。结论在空腹和餐后条件下,索磷布韦片受试制剂与参比制剂具有生物等效性。Objective To investigate the pharmacokinetic characteristics of sofosbuvir tablets,and to evaluate the bioequivalence and safety of two preparations.Methods Healthy volunteers were recruited through the platform of clinical trial recruitment in The Affiliated Hospital of Changchun University of Chinese Medicine.Screening physical examination was performed for fasting group on September 18,2018 and for postprandial group on September 28,2018,and the volunteers were enrolled after their physical examination results met the inclusion criteria.The fasting group and the postprandial group,with 40 volunteers in each group,were given oral administration of the test preparation sofosbuvir tablets or the reference preparation sofosbuvir tablets(SOVALDI,400 mg).This was a randomized,open-label,two-sequence,four-cycle,single-dose,and completely repeated cross-over bioequivalence test in the fasting or postprandial state in the healthy population;in the fasting group,20 volunteers each received oral administration of the test preparation and the reference preparation,and in the postprandial group,20 volunteers each received oral administration of the test preparation and the reference preparation.Liquid chromatography-tandem mass spectrometry was used to measure the content of sofosbuvir and its major metabolite GS-331007 in human EDTA-K2 plasma;the plasma concentration of sofosbuvir was measured at 15 time points from 0 hour to 8 hours after administration,and that of GS-331007 was measured at 16 time points from 0 hour to 72 hours after administration.WinNonlin software was used to calculate pharmacokinetic parameters and evaluate bioequivalence.Results After the administration of the test preparation and the reference preparation in the fasting state,when the pharmacokinetic parameters of sofosbuvir was used to evaluate the bioequivalence of the test preparation and the reference preparation,the ratios of the geometric means of Cmax,AUC0-t,and AUC0-inf were 90.55%,97.26%,and 94.62%,respectively;when the pharmacokinetic pa

关 键 词：丙型肝炎 抗病毒药 索磷布韦 治疗等效 串联质谱法 

分 类 号：R512.63[医药卫生—内科学] R969[医药卫生—临床医学]