依托考昔片在中国健康受试者的药动学及安全性研究

Study on Pharmacokinetics and Safety of Etoricoxib Tablets in Chinese Healthy Subjects

关键词:  依托考昔  药动学  安全性  生物等效性

Key words:  etoricoxib  pharmacokinetics  safety  bioequivalence

摘要:

目的 研究中国健康受试者空腹、餐后单次口服依托考昔片的药动学及安全性。方法 将68例健康受试者随机分为空腹组和餐后组，采用双周期交叉试验设计进行给药，LC-MS/MS测定人血浆中依托考昔浓度，用WinNonLin软件计算药动学参数，比较国产依托考昔片和原研参比制剂药动学差异以及不同性别和进食对托考昔片药动学的影响。以受试者生命体征及体格检查、实验室检查值以及心电图变化为指标进行依托考昔片安全性评价。结果 空腹组受试制剂和参比制剂的药动学参数T_max为1.25，1.25 h，C_max为（2 767.50±421.89），（2 707.81±674.90） ng·mL^-1，AUC_0-∞为（52 967.87±13 843.25），（53 479.56±16 066.32） h·ng·mL^-1；餐后组受试制剂和参比制剂的药动学参数T_max为2.50，1.75 h，C_max为（2 000.61±314.89），（2 209.06±429.05） ng·mL^-1，AUC_0-∞为（51 450.80±17 241.02），（49 287.23±16 192.87） h·ng·mL^-1；餐后组受试制剂和参比制剂T_max差异具有统计学意义（P<0.05），但不具有临床意义。受试者空腹、餐后口服依托考昔片后，T_max、C_max差异具有统计学意义（P<0.01），但AUC_0-∞差异无统计学意义；不同性别受试者空腹口服依托考昔片后，主要药动学参数T_max、C_max、AUC_0-∞均无统计学意义，但女性受试者餐后口服依托考昔片后t_1/2、AUC_0-∞较男性受试者高（P<0.05）。空腹和餐后给药后不良事件涉及多系统，均为轻度，无严重不良反应。结论 国产依托考昔片和原研参比制剂具有生物等效性；进食影响依托考昔片的吸收速度，但不影响其吸收程度；空腹给药后依托考昔片的药动学参数无性别差异，但餐后给药后t_1/2、AUC_0-∞存在性别差异。依托考昔片在中国健康受试者中具有良好的安全性和耐受性。

Abstract:

OBJECTIVE To study the pharmacokinetics and safety of etoricoxib in Chinese healthy subjects following single oral administration under fasting and fed conditions. METHODS Sixty-eight healthy subjects were randomly divided into a fasting group and a fed group, and administered using a 2-period crossover trial design, LC-MS/MS was used to determine the concentration of etoricoxib in human plasma. The pharmacokinetic parameters were calculated using WinNonLin software, to compare the pharmacokinetic differences between domestic etoricoxib and original reference preparations, and the effects of different genders and meals on the pharmacokinetic parameters of etoricoxib were compared. The safety of etoricoxib tablets was evaluated by vital signs, physical examination, laboratory test results and electrocardiogram changes. RESULTS The pharmacokinetic parameters of the test and reference preparations in the fasting group were as follows:T_max 1.25, 1.25 h, C_max (2 767.50±421.89), (2 707.81±674.90)ng·mL^-1, AUC_0-∞ (52 967.87±13 843.25), (53 479.56±16 066.32)h·ng·mL^-1. The pharmacokinetic parameters of the test and reference preparations in the fed group were as follows:T_max 2.50, 1.75 h, C_max (2 000.61±314.89), (2 209.06±429.05)ng·mL^-1, AUC_0-∞ (51 450.80±17 241.02), (49 287.23±16 192.87)h·ng·mL^-1. There was a statistically significant difference in T_max between the test and reference preparations in the fed group(P<0.05), but it has no clinical significance. After the subjects took oral etoricoxib tablets on an empty stomach and after meals, there was a statistically significant difference in T_max and C_max(P<0.01), but there was no statistically significant difference in AUC_0-∞. There was no significant difference in the main pharmacokinetic parameters T_max, C_max, and AUC_0-∞ among subjects of different genders after oral administration of etoricoxib tablets under fasting condition, but t_1/2 and AUC_0-∞ were higher in female subjects compared with male subjects after postprandial administration(P<0.05). Adverse events after fasting and postprandial administration involve multiple systems and were mild without serious adverse reactions. CONCLUSION Domestic etoricoxib tablets and original reference preparations have bioequivalence; meals affect the absorption rate of etoricoxib tablets, but do not affect the extent of absorption; there are no gender differences in pharmacokinetic parameters of etoricoxib after fasting administration, but there are gender differences in t_1/2, AUC_0-∞ after postprandial administration. Etoricoxib tablets have good safety and tolerance in Chinese healthy subjects.