高剂量异烟肼、利福喷丁在健康汉族人群中的药代动力学及安全性研究  

Pharmacokinetics and safety of high-dose isoniazid and rifapentine in healthy han population:A bio-equivalence trial

作　　者：袁媛 马嘉烨 刘旭晖 夏露 刘萍 贾晓龙 卢水华 YUAN Yuan;MA Jia-ye;LIU Xu-hui;XIA Lu;LIU Ping;JIA Xiao-long;LU Shui-hua(Shanghai Public Health Clinical Center,Fudan University,Shanghai 201508,China)

机构地区：[1]复旦大学附属上海市公共卫生临床中心,201508

出　　处：《中国防痨杂志》2021年第12期1314-1321,共8页Chinese Journal of Antituberculosis

基　　金：上海市临床重点专科建设项目(shslczdzk03002)。

摘　　要：目的评价高剂量异烟肼、利福喷丁在健康汉族人群中的药代动力学表现以及安全性,为实施结核病预防性治疗提供临床证据。方法2019年10—12月上海市公共卫生临床中心招募36名健康受试者,按1∶1随机区组分为国产制剂组(T组)18名和参比制剂组(R组)18名,T组单次口服国产异烟肼、利福喷丁各900 mg,R组单次口服异烟肼、利福喷丁参比制剂各900 mg,每组随机一半受试者空腹服药(T1组9名,R1组9名),另一半受试者餐后服药(T2组9名,R2组9名)。服药后在规定时间点采集静脉血并分离血浆,采用液相色谱-串联质谱法(LC-MS)测定血浆中的药物及代谢物浓度,采用Phoenix WinNonlin 8.1软件计算药代动力学参数,并记录72 h观察期内所有不良事件。结果T1组和R1组比较,利福喷丁的峰浓度C_(max)分别为(21.2±7.3)μg/ml和(15.2±2.8)μg/ml(t=3.256,P=0.003),AUC_(0~t)分别为(624.3±327.4)μg·h/ml和(479.4±141.8)μg·h/ml(t=1.724,P=0.094);异烟肼的C_(max)分别为(29.9±4.5)μg/ml和(25.2±6.8)μg/ml(t=2.445,P=0.020);AUC_(0~t)分别为(80.7±21.4)μg·h/ml和(80.4±12.7)μg·h/ml(t=0.051,P=0.960)。T2组和R2组比较,利福喷丁的C_(max)分别为(25.4±6.8)μg/ml和(26.5±5.2)μg/ml(t=-0.545,P=0.589),AUC_(0~t)分别为(756.4±253.2)μg·h/ml和(779.7±175.5)μg·h/ml(t=-0.321,P=0.750);异烟肼的C_(max)分别为(11.5±1.6)μg/ml和(10.9±1.5)μg/ml(t=1.161,P=0.253),AUC_(0~t)分别为(54.2±9.3)μg·h/ml和(55.8±8.9)μg·h/ml(t=-0.527,P=0.602)。T1组与R1组利福喷丁的C_(max)、AUC_(0~t)几何均数比值的90%CI分别为102.7%~158.9%和87.4%~169.0%,异烟肼的C_(max)、AUC_(0~t)几何均数比值的90%CI分别为100.0%~147.8%和80.9%~120.4%;T2组与R2组利福喷丁的C_(max)、AUC_(0~t)几何均数比值的90%CI分别为78.3%~113.6%和74.3%~119.5%,异烟肼的C_(max)、AUC_(0~t)几何均数比值的90%CI分别为91.8%~120.8%和82.1%~114.6%。未见严重不良事件报告。结论根据两组药代动力学指标的几何均数的90%CI,Objective To evaluate the pharmacokinetic performance and safety of high does of isoniazid and rifapentine in healthy Han population,to provide clinical evidence for preventive therapy of tuberculosis.Methods From October to December 2019,a pharmacokinetic clinical trial was carried out at the Shanghai Public Health Clinical Center.36 healthy subjects were randomly allocated into a domestic drug group(T)and a reference drug group(R)at a ratio of 1∶1.Subjects in Group T were given a single dose oral administration of 900 mg domestic isoniazid and 900 mg domestic rifapentine,Subjects in Group R were given 900 mg reference isoniazid and 900 mg reference rifapentine.Half of the patients in each group were randomly chosen to take those drugs before meals(T1,R1),and the other half would take drugs after meals(T2,R2).After taking the drug,venous blood samples were collected at specified time points and the plasma were separated.Liquid chromatography-tandem mass spectrometry(LC-MS)was used to determine the concentration of drugs and their metabolites in the plasma.Phoenix WinNonlin 8.1 was used to calculate the pharmacokinetic parameters and record all adverse events during the observation period for 72 hours.Results For T1 and R1 group,the peak concentration(C_(max))of rifapentin were(21.2±7.3)μg/ml and(15.2±2.8)μg/ml,respectively(t=3.256,P=0.003);area under the plasma concentration curve from administration to last observed concentration at time t(AUC_(0-t))were(624.3±327.4)μg·h/ml and(479.3±141.8)μg·h/ml(t=1.724,P=0.094);C_(max) of isoniazid were(29.9±4.5)μg/ml and(25.2±6.8)μg/ml(t=2.445,P=0.020);AUC_(0-t) were(80.7±21.4)μg·h/ml and(80.4±12.7)μg·h/ml(t=0.051,P=0.960).For T2 and R2 groups,the C_(max) of rifapentine were(25.4±6.8)μg/ml and(26.5±5.2)μg/ml(t=-0.545,P=0.589);AUC_(0-t) were(756.4±253.2)μg·h/ml and(779.7±175.5)μg·h/ml(t=-0.321,P=0.750);the C_(max) of isoniazid were(11.5±1.6)μg/ml and(10.9±1.5)μg/ml(t=1.161,P=0.253);AUC_(0-t) were(54.2±9.3)μg·h/ml and(55.8±8.9)μg·h/ml

关 键 词：异烟肼 利福喷丁 药代动力学 临床试验 

分 类 号：R969.1[医药卫生—药理学]