摘要
目的研究受试者口服环孢素软胶囊受试制剂和参比制剂后的药代动力学,并评价两制剂的生物等效性。方法采用单中心、开放、随机、两序列、四周期重复交叉空腹/餐后口服给药的试验设计。空腹及餐后生物等效性试验分别纳入8例健康受试者,并随机分为2组,每组4例;口服环孢素软胶囊受试制剂(T)和参比制剂(R) 50 mg,第一组按照TRTR的给药序列,第二组按照RTRT的给药序列。用液相色谱-质谱串联法测定血浆中环孢素浓度,通过Phoenix Win Nonlin(Pharsight Corporation) 6.3版和SAS 9.4版进行药代动力学参数计算;通过平均生物等效性(ABE)和参比制剂标度的平均生物等效性(RSABE)的评价方法考察受试制剂和参比制剂的生物等效性。结果空腹口服受试制剂和参比制剂后,全血中环孢素的t;分别为(6.99±0.71)和(7.05±0.69) h,C;分别为(339.14±72.16)和(344.22±86.41) ng·m L^(-1),AUC;分别为(923.03±251.25)和(930.11±242.11) h·ng·m L^(-1),AUC;分别为(965.21±268.08)和(973.14±259.01) h·ng·m L^(-1);餐后口服受试制剂和参比制剂后,全血中环孢素的t;分别为(6.50±1.02)和(6.64±0.56) h,C;分别为(232.02±103.07)和(230.08±83.49) ng·m L^(-1),AUC;分别为(729.11±212.20)和(714.04±177.08) h·ng·m L^(-1),AUC;分别为(761.24±218.05)和(743.15±184.13) h·ng·m L^(-1)。采用ABE的统计方法评价时,受试制剂与参比制剂C;、AUC;及AUC;几何均值比对应的90%置信区间均符合等效范围要求(80.00%~125.00%)。采用RSABE方法评价时,(Y;-Y;);-θS;的95%置信区间上限值均小于0,且药代动力学参数的受试制剂与参比制剂个体内标准差比值的90%置信区间上限值小于2.5。结论结果表明两种制剂间无显著性差异,具有生物等效性。
Objective The pharmacokinetics of the test and reference preparations of cyclosporine soft capsules taken by the study subjects was studied,and the bioequivalence of the two preparations was evaluated.Methods A single-center,open,randomized,two-sequence,four-cycle repeated crossover fasting/post-meal oral administration trial design was adopted.Fasting and postprandial bioequivalence trials were enrolled in 8 healthy subjects and randomly divided into 2 groups with 4cases in each group;oral cyclosporine soft capsule test preparation (T)and reference preparation (R) 50 mg,the first group follows the TRTR dosing sequence,and the second group follows the RTRT dosing sequence.Determine the concentration of cyclosporine in plasma by LC-MS/MS method.The pharmacokinetic parameters were calculated by Phoenix WinNonlin (Pharsight Corporation) version 6.3 and SAS version 9.4;the bioequivalence of test and reference preparations were investigated by average bioequivalence (ABE) and referencescaled average bioequivalence (RSABE).Results After oral administration of the test and reference preparations on an empty stomach,the t;of cyclosporine in the whole blood were (6.99±0.71) and (7.05±0.69) h,respectively;and the C;were (339.14±72.16) and (344.22±86.41) ng·mL^(-1)respectively;AUC;were (923.03±251.25)and (930.11±242.11) h·ng·mL^(-1)respectively;AUC;were (965.21±268.08) and (973.14±259.01)h·ng·mL^(-1)respectively.After oral administration of the test and reference preparations after a meal,the t;of cyclosporine in the whole blood were (6.50±1.02) and (6.64±0.56) h respectively;C;were (232.02±103.07)and (230.08±83.49) ng·mL^(-1)respectively,AUC;were (729.11±212.20) and (714.04±177.08)h·ng·mL^(-1)respectively;AUC;were (761.24±218.05) and (743.15±184.13) h·ng·mL^(-1)respectively.The results of the bioequivalence test show that when the ABE statistical method is used for evaluation,the test preparation and the reference preparation C;,AUC;,and AUC;geometric mean ratio meets the requirement of equivalent
作者
程林
张娴
李玉凤
张慧明
李彦朴
侯杰
CHENG Lin;ZHANG Xian;LI Yu-feng;ZHANG Hui-ming;LI Yan-pu;HOU Jie(North China Pharmaceutical Co.Ltd,Shijiazhuang 052165,Hebei Province,China;Perking University Care Luzhong Hospital Phase I Center,Zibo 255400,Shandong Province,China)
出处
《中国临床药理学杂志》
CAS
CSCD
北大核心
2022年第4期342-346,共5页
The Chinese Journal of Clinical Pharmacology
