硫唑嘌呤片在中国健康受试者空腹状态下的生物等效性

Bioequivalence of azathioprine tablets in the healthy Chinese volunteers under fasting condition

目的评价国产硫唑嘌呤片与原研片剂在中国健康受试者中空腹条件下的生物等效性及安全性。方法采用单中心、随机、开放、单剂量、两序列、四周期、完全重复交叉给药设计,入组36例健康男性和女性受试者,随机分为2组。每周期单次空腹口服硫唑嘌呤受试制剂或参比制剂50 mg。用HPLC-MS/MS法测定血浆中硫唑嘌呤及6-巯基嘌呤的浓度。用Phoenix WinNonlin 8.2软件进行药代动力学参数的估算和生物等效性评价。结果空腹状态下口服硫唑嘌呤片受试制剂和参比制剂后,硫唑嘌呤的C_(max)分别为(17.81±7.36)和(17.76±6.94)ng·mL^(-1),AUC_(0-t)分别为(17.41±3.65)和(17.03±3.94)h·ng·mL^(-1),AUC_(0-∞)分别为(17.58±3.69)和(17.72±3.82)h·ng·mL^(-1);受试制剂和参比制剂的6-巯基嘌呤C_(max)分别为(29.23±16.91)和(28.18±16.80)ng·mL^(-1),AUC_(0-t)分别为(54.26±19.18)和(52.15±20.38)h·ng·mL^(-1),AUC_(0-∞)分别为(55.45±19.42)和(53.39±20.31)h·ng·mL^(-1);受试制剂与参比制的硫唑嘌呤及6-巯基嘌呤C_(max)的S_(WR)均大于0.294,其点估值均落在80.00%~125.00%且(μT-μR)^(2)-θS^(2)_(WR)的单侧95%置信区间上限小于0;AUC_(0-t)、AUC_(0-∞)的S_(WR)均小于0.294,经对数转换后的几何均数的比值相对应的90%置信区间均落在80.00%~125.00%,符合生物等效性要求。整个试验过程中不良事件发生率为63.89%,其中受试制剂/参比制剂与研究药物相关的不良事件发生率分别为40.00%和37.14%。本试验中无严重不良事件发生,受试制剂不良事件严重程度2例次为Ⅱ级,其余为Ⅰ级,参比制剂所有不良事件严重程度均为Ⅰ级。所有结果均为改善或恢复。结论硫唑嘌呤片受试制剂与参比制剂在中国健康受试者中空腹状态下具有生物等效性,在中国健康受试者中安全性及耐受性良好。

Objective To evaluate the bioequivalence and safety of the domestic and original azathioprine tables in fasting state in Chinese healthy volunteers.Methods A single-center,randomized,open,single-dose,two-sequence,four-period,fully repetitive crossover design was used.In this study,36 healthy male and female subjects were randomly divided into two groups.After a single oral dose of azathioprine test or reference 50 mg in fasting state for per period,HPLC-MS/MS method was used to determine the concertration of azathioprine and 6-mercaptopurine in plasma.The pharmacokinetic parameters were caculated.Bioequivalence was evaluated by Phoenix WinNonlin 8.2 software.Results After oral administration of azathioprine tables in fasting state,the main pharmacokinetic parameters of the test and reference azathioprine tables were as follows:C_(max)(17.81±7.36)and(17.76±6.94)ng·mL^(-1),AUC_(0-t)(17.41±3.65)and(17.03±3.94)h·ng·mL^(-1),AUC_(0-∞)(17.58±3.69)and(17.72±3.82)h·ng·mL^(-1).The main pharmacokinetic parameters of the test and reference 6-mercaptopurine tables were as follows:C_(max)(29.23±16.91)and(28.18±16.80)ng·mL^(-1),AUC_(0-t)(54.26±19.18)and(52.15±20.38)h·ng·mL^(-1),AUC_(0-∞)(55.45±19.42)and(53.39±20.31)h·ng·mL^(-1).For azathioprine and 6-mercaptoprine,the S_(WR) of C_(max)>0.294,and the 90%confidence interval for the ratio of C_(max) met the predetermined criteria for assuming bioequivalence(80.00%-125.00%)and the(μT-μR)^(2)-θS 2 WR<0;the S_(WR)of AUC_(0-t)、AUC_(0-∞)<0.294.The 90%confidence intervals for the ratios of AUC_(0-t) and AUC_(0-∞)all met the predetermined criteria for assuming bioequivalence(80.00%-125.00%),and all met the requirement of bioequivalence.During the whole trial,the incidence of adverse events was 63.89%,of which 40.00%and 37.14%was related to test and reference drug,and no serious adverse events occurred.The adverse events of test preparation was gradeⅡin 2 case and gradeⅠin the rest.All adverse events of reference preparation were gradeⅠ,and the results were improvement or recovery.Conclusion The test and reference azathioprine tables were bioequivalent and were safe and well tolerated in fasting state in Chinese healthy subjects.