国产替吉奥片剂在恶性肿瘤患者中的生物等效性研究

Bioequivalence of Tegafur,Gimeracil,and Oteracil Potassium Tablets in Cancer Patients

目的:研究国产替吉奥片剂在恶性肿瘤患者体内的生物等效性。方法:采用多中心、开放、随机、双周期交叉试验设计,29例恶性肿瘤患者分别口服替吉奥片剂或替吉奥胶囊(S-1),2个周期间的清洗期为1周。多点采集血样,采用液相色谱-质谱-质谱联用法测定替加氟、5-氟尿嘧啶(5-FU)、吉美嘧啶(CDHP)和奥替拉西(Oxo)的血药浓度,采用Phoenix WinNonlin 6.1药动学软件进行药动学参数分析和计算。结果:受试者口服受试制剂和参比胶囊后,血浆中替加氟C_(max)分别为(2 080±601)ng·mL^(-1)和(2 050±615)ng·mL^(-1),AUC_(last)分别为(25 300±10 900)ng·h·mL^(-1)和(24 600±11 600)ng·h·mL^(-1);5-氟尿嘧啶C_(max)分别为(161±73.5)ng·mL^(-1)和(166±79.9)ng·mL^(-1),AUC_(last)分别为(829±506)ng·h·mL^(-1)和(824±415)ng·h·mL^(-1);吉美嘧啶C_(max)为(351±141)ng·mL^(-1)和(334±143)ng·mL^(-1),AUC_(last)(1 570±914)ng·h·mL^(-1)和(1 550±868)ng·h·mL^(-1);奥替拉西C_(max)(68.4±62.4)ng·mL^(-1)和(56.2±39.9)ng·mL^(-1),AUC_(last)(243±185)ng·h·mL^(-1)和(241±172)ng·h·mL^(-1)。AUC和C_(max)经对数转换后进行方差分析及90%置信区间判断,替吉奥片与S-1胶囊C_(max)几何均值比的90%置信区间为75%～133%,AUC_(last)几何均值比的90%置信区间为80%～125%;T_(max)无显著性差异(P<0.01)。本试验剂量下替吉奥片剂和S-1胶囊耐受性良好,无严重不良事件。结论:替吉奥片剂与S-1胶囊在人体内具有相似的体内过程和药代动力学特征。符合生物等效的相关要求,可判断替吉奥片剂与S-1胶囊具有生物等效性。

Objective： This study analyzes the bioequivalence of tegafur, gimeracil, and teracil potassium tablets in cancer patients. Methods： Twenty-nine patients were given 60 mg single dose and reference formulations based on an open-randomized two-way crossover design. The plasma concentrations of tegafur （FT）, 5-fluorouracil （5-FU）, gimeracil （CDHP）, and oxonic acid （Oxo） were determined by liquid chromatography/tandem mass spectrometry. Results： The main pharmacokinetic parameters of the test and reference formulations include a maximum concentration （Cmax） and area under curvelast （AUClast） for FT were 2 080 ng/mL 601 ng/mL and 2 050 ng/mL 615 ng/ mL and 25 300 ng. h/mL 10 900 ng. h/mL and 24 600 ng. h/mL 11 600 ng. h/mL, respectively. The values of Cmax and AUClast for 5-FU were 161 ng/mL 73.5 ng/mL and 166 ng/mL 79.9 ng/mL and 1570 ng/mL 914 ng.b/mL and 1550 ng.h/mL 868 ngh/mL, respectively. The values of Cmax and AUClast for CDHP were 351 ng/mL 141 ng/mL and 334 ng/mL 143 ng/mL and 1 570 ng. h/mL 914 ng-h/mL and 1 550 ng. h/mL 868 ng. h/mL, respectively. The values of Cmax and AUClast for Oxo were 68.4 ng/mL 62.4 ng/mL and 56.2 ng/mL 39.9 ng/mL and 243 ng-h/mL 185 ngh/mL and 241 ng·h/mL 172 ng. h/mL, respectively. The 90% confidence interval （CI） of the geometric mean ratio of AUClast for the test and reference formulations was between 80% and 125%. The 90% CI of the geometric mean ratio of Cmax was between 75% and 133%. No significant differences were found for the Tmax between the groups （P〈0.01）. Tolerance of the test and reference formulations was favorable under the test dose. NO serious adverse events were observed. Conclusion： The results demonstrate that the two formulations are bioequivalent by analysis of variance.