吡嗪酰胺片高脂餐后服用在健康受试者中的生物等效性和安全性

Bioequivalence and safety of pyrazinamide tablets after high-fat meal in healthy subjects

目的评价健康受试者高脂餐后口服吡嗪酰胺片的生物等效性和安全性。方法采用单中心、随机、开放、两周期、双交叉设计的生物等效性研究,将受试者随机分为受试制剂-参比制剂组和参比制剂-受试制剂组,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ULTRAtab Laboratories,Inc.生产的Pyrazinamide^(®),分别在第1天和第8天高脂餐后接受1次受试制剂和1次参比制剂500 mg,比较2种制剂的生物等效性。周期之间的洗脱期为7 d。按方案规定的时间点采集生物样本进行血药浓度的分析,对吡嗪酰胺的主要药代动力学参数血药峰浓度(C_(max))、从0时至t时血药浓度-时间曲线下面积(AUC_(0~t))和0时至无穷大的血药浓度-时间曲线下面积(AUC_(inf))进行等效性评价。结果24名受试者纳入研究,包括男16名(66.7%)、女8名(33.3%),年龄(35±9)岁。24名均完成2次给药及随访。生物等效性研究结果显示,2种吡嗪酰胺片高脂餐后试验,主要药代动力学参数C_(max)、AUC_(0~t)和AUC_(inf)的几何均数比值分别为97.00%、98.80%、98.70%,90%置信区间分别为92.91%~101.27%、96.52%~101.13%和96.35%~101.11%,均落在常规生物等效80.00%~125.00%范围内。研究期间2组受试者均未发生导致退出研究的不良事件和严重不良事件。结论2种吡嗪酰胺片制剂在高脂餐后的健康受试者中具有生物等效性,安全性良好。

Objective To evaluate the bioequivalence and safety of pyrazinamide tablets orally after eating high-fat meal in healthy subjects.Methods A single-center,randomized,open,two-period,and two-crossover design bioequivalence study was performed.Subjects were randomly divided into test-reference preparations group and reference-test preparations group.The test preparation was pyrazinamide tablets produced by Taicang Pharmaceutical Factory;the reference preparation Pyrazinamide^(®) was produced by ULTRAtab Laboratories,Inc.,America.Subjects in the two groups were given the test preparation or the reference preparation 500 mg after high-fat meal on the 1 st and 8 th day,respectively.The bioequivalence of the two preparations was compared.The washout period between cycles was 7 d.Biological samples were collected at the protocol scheduled time points for blood concentration analysis.The equivalence of the main pharmacokinetic parameters of pyrazinamide was evaluated:peak blood concentration(C_(max)),the area under the curve from time 0 to t(AUC_(0-t))and the area under the curve from time 0 to infinity(AUC_(inf)).Results Twenty-four subjects were included in this study,including 16 males(66.7%)and 8 females(33.3%),aged(35±9)years.All subjects completed 2 times of drug administration and follow-up.The results of bioequivalence study showed that the geometric mean ratios of main pharmacokinetic parameters C_(max),AUC_(0-t) and AUC_(inf) of the two pyrazinamide tablets were 97.00%,98.80%and 98.70%,and90%confidence interval were 92.91%-101.27%,96.52%-101.13%and 96.35%-101.11%,respectively,within the regular bioequivalence range 80.00%-125.00%.During the study period,there were no adverse events leading subjects withdrawal or serious adverse events in both groups.Conclusion The two pyrazinamide tablets preparations are bioequivalent in healthy subjects after high-fat meal and have good safety.