国产与原研吡嗪酰胺片空腹状态下服用的生物等效性和安全性研究  

Fasting bioequivalence and safety assessment of domestic versus original pyrazinamide tablets

作　　者：所伟[1] 荆珊[1] 刘文芳[1] 鲁春艳[1] 杨克旭[1] 刘敬怡 谭莉[1] 李静[1] 赵桂平[1] 林阳[1] Suo Wei;Jing Shan;Liu Wenfang;Lu Chunyan;Yang Kexu;Liu Jingyi;Tan Li;Li Jing;Zhao Guiping;Lin Yang(Department of Pharmacy,Beijing Anzhen Hospital,Capital Medical University,Beijing 100029,China)

机构地区：[1]首都医科大学附属北京安贞医院药事部,北京100029

出　　处：《药物不良反应杂志》2022年第6期295-299,共5页Adverse Drug Reactions Journal

基　　金：国家科技重大专项(2017ZX09304017)。

摘　　要：目的评价国产与原研吡嗪酰胺片空腹状态下服用的生物等效性和安全性。方法采用单中心、随机、开放、2周期、自身交叉试验设计,受试制剂为太仓制药厂生产的吡嗪酰胺片,参比制剂为美国安士制药有限公司生产的吡嗪酰胺片(Pyrazinamide©)。将健康受试者随机分为2组,每组均服药2个周期,但服用受试制剂(T)和参比制剂(R)的顺序不同,分别为R⁃T和T⁃R组。受试者分别在试验第1、8天空腹服用1片(500 mg)受试或参比制剂。生物等效性评价以药代动力学参数为终点评价指标。每次服药前1 h内以及服药后15、30、45、60、75、90、105、120、150、180、210 min和4、5、6、8、12、24、36、48 h采集受试者外周静脉血3 ml,离心后取血浆冻存。应用串联液相色谱-质谱法测定血浆样品中吡嗪酰胺的浓度,计算血药峰浓度(C_(max))、血药浓度-时间曲线下面积[AUC,包括从0时至最后一个浓度可准确测定的样品采集时间t的AUC(AUC_(0⁃t))和从0时至无限时间的AUC(AUC_(0⁃∞))]等主要药代动力学参数。受试制剂与参比制剂C_(max)、AUC_(0⁃t)和AUC_(0⁃∞)几何均值比值的90%置信区间(CI)介于0.80~1.25为等效。观察并记录受试者试验期间不良事件发生情况。结果纳入试验的健康受试者共24例,男性16例,女性8例;年龄18~50岁。R⁃T组和T⁃R组各12例,所有受试者均完成试验。空腹口服后受试制剂和参比制剂C_(max)、AUC_(0⁃t)和AUC_(0⁃∞)几何均值比值的90%CI分别为0.93~1.09、0.98~1.03和0.98~1.03。试验期间受试者不良事件发生率为25.0%(6/24),发生在服用受试制剂和参比制剂后者各3例,严重程度均为1级。结论国产与原研吡嗪酰胺片空腹状态下服用具有生物等效性和良好的安全性。Objective To evaluate the bioequivalence and safety of domestic and original pyra⁃zinamide tablets under fasting condition.Methods A single center,randomized,open⁃label,two period self⁃crossover trial was conducted in healthy adult volunteers.The test preparation(T)of pyrazinamide tablets was produced by Taicang Pharmaceutical Factory and the reference preparation(R)was produced by A&Z Pharmaceutical Inc.(Pyrazinamide©).The healthy subjects were randomly divided into 2 groups and took the drugs for 2 times with different order in each group,which were R⁃T group(subjects took R on day 1 and then T on day 8)and T⁃R group(subjects took T on day 1 and then R on day 8).Pharmacokinetic parameters were used as endpoints to assess the bioequivalence.Peripheral venous blood samples(3 ml)were collected from subjects within 1 hour before taking the drug and at 15,30,45,60,75,90,105,120,150,180,and 210 minutes and 4,5,6,8,12,24,36,and 48 hours after taking the drug.Plasma was frozen after centrifugation of the blood samples.The plasma pyrazinamide concentrations were determined by a tandem liquid chromatography⁃mass spectrometry method and the main pharmacokinetic parameters such as peak concentration(C_(max))and the area under the concentration⁃time curve(AUC),including AUC from time zero(pre⁃dose)to the time of the last quantifiable concentration(AUC_(0⁃t))and AUC from time zero to infinity(AUC_(0⁃∞)),were calculated.The test and reference preparations were judged as bioequivalence when the 90%confidence intervals(CI)of geometric mean ratios for AUC_(0⁃t),AUC_(0⁃∞),and C_(max) all ranged from 0.80 to 1.25.Adverse events occurred in subjects during the trial were observed and recorded.Results A total of 24 healthy volunteers were enrolled in the trial,including 16 males and 8 females aged 18⁃50 years,with 12 in the R⁃T and T⁃R groups,respectively.All subjects completed the trial.After taking medicine under fasting condition,the 90%CI of the geometric mean ratios of C_(max),AUC_(0⁃t),and

关 键 词：吡嗪酰胺 等效性试验 药代动力学 安全性 

分 类 号：R969.3[医药卫生—药理学]