盐酸美金刚口溶膜在中国健康人体的生物等效性研究

Bioequivalence of Memantine Hydrochloride oral soluble film in Chinese healthy volunteers

目的研究健康成年受试者空腹和餐后状态下单次口服受试制剂盐酸美金刚口溶膜(OSF)与参比制剂盐酸美金刚口服溶液(OS)的生物等效性。方法试验分空腹和餐后2个试验:空腹试验采用随机、开放、三周期、三序列、交叉设计,受试者按照1∶1∶1分别随机分为3组,分别为单次不给水或给水条件下口服受试制剂OFS 1片(10 mg)或单次给水条件下口服参比制剂OS 1 mL(10 mg);餐后试验采用随机、开放、两周期、两序列、交叉设计,受试者按照1∶1分别随机分为2组,分别为单次给水条件下口服受试或参比制剂OS 1 mL(10 mg);用液相色谱-串联质谱(LC-MS/MS)法测定血浆中美金刚的浓度,用WinNonlin■8.2软件计算药代动力学参数,用SAS 9.4软件进行药代动力学参数的统计分析评价生物等效性。结果空腹试验不给水条件下、给水条件下服用受试制剂或给水条件下服用参比制剂后,美金刚药代动力学参数:C_(max)分别为(18.23±3.52)、(18.88±4.27)、(18.56±3.38)ng·mL^(-1),AUC_(0-72 h)分别为(742.57±118.30)、(742.85±124.42)、(739.77±109.18)ng·mL^(-1)·h;餐后试验给水条件下服用受试制剂或服用参比制剂后,美金刚药代动力学参数:C_(max)分别为(18.98±3.51)、(18.54±2.90)ng·mL^(-1),AUC_(0-72 h)分别为(741.45±143.18)、(728.15±129.65)ng·mL^(-1)·h。空腹不给水条件下受试制剂和参比制剂的C_(max)和AUC_(0-72 h)经对数转换后90%可信区间分别为95.48%~101.07%和97.77%~101.45%;空腹给水条件下受试制剂和参比制剂的C_(max)和AUC_(0-72 h)经对数转换后90%可信区间分别为97.79%~103.43%和97.23%~100.84%;餐后给水条件下受试制剂和参比制剂的C_(max)和AUC_(0-72 h)经对数转换后90%可信区间分别为99.23%~103.88%和99.56%~103.12%。结论受试制剂和参比制剂在中国健康受试者体内具有生物等效性。

Objective To study the bioequivalence of test Memantine Hydrochloride oral soluble film(OSF)and reference Memantine Hydrochloride oral solution(OS)in healthy adult subjects on fasting and fed conditions.Methods This study consisted of two trials:a randomized,open-label,single-dose,3-sequence,3-period crossover trial under fasting conditions and a randomized,open-label,single-dose,2-sequence,2-period crossover trial under fed conditions.Healthy volunteers were randomized 1∶1∶1 to receive single-dose oral Memantine Hydrochloride OSF(1 piece,10 mg)without and w ith water, or OS (1 mL, 10 mg) with water in the fasting trial, and 1∶ 1 to receive OSF (1 piece, 10 mg) or OS(1 mL, 10 mg) with water in the fed trial in each period. The plasma concentration of memantine was determined byLC - MS/ MS, and the PK parameters was calculated by WinNonlin® 8. 2 software, and the bioequivalence wasevaluated by SAS 6. 4 software. Results The main pharmacokinetic parameters of the memantine in the fastingconditions for OSF without and with water, or OS with water were as follows: C_(max) were (18.23 ±3.52), (18.88 ±4.27),(18. 56 ±3. 38) ng · mL^(-1);AUC_(0-72 h) were (742. 57 ± 118. 30), (742. 85 ± 124. 42), (739. 77 ± 109. 18)ng·mL^(-1)·h. The main pharmacokinetic parameters of the memantine in the fed conditions for OSF and OS with waterwere as follows: C_(max) were (18. 98 ± 3. 51), (18. 54 ± 2. 90) ng·mL^(-1);AUC_(0-72 h) were (741. 45 ± 143. 18),(728. 15 ±129. 65) ng·mL^(-1) ·h. The 90% confidential interval of the geometric mean ratio of C_(max) and AUC_(0-72 h)for memantine hydrochloride OSF without water and OS with water in the fasting conditions were 95. 48% -101. 07%and 97. 77% -101. 45%, OSF and OS with water in the fasting conditions were 97. 79% -103. 43% and 97. 23% -100. 84%;the 90% confidential interval of the geometric mean ratio of C_(max), and AUC_(0-72 h) for memantinehydrochloride OSF and OS with water in the fed conditions were 99. 23% - 103. 88% and 99. 56% - 103. 12% .Conclusion The test preparation and the reference preparation were bioequivalent in fasting and fed conditions.