两种咪唑斯汀缓释制剂体内生物利用度和药动学研究

摘要

目的 对两种上市的咪唑斯汀缓释制剂进行人体药动学的研究,以评价两厂家生产的咪唑斯汀缓释片是否具有生物等效性.方法 采用随机交叉试验设计,10名男性健康受试者单剂量口服咪唑斯汀缓释片(皿治林和尼乐)10 mg后于规定时间点取血,用高效液相法测定血药浓度,计算两种缓释制剂的主要药动学参数,进行人体生物利用度的比较.结果 10名男性健康受试者单剂量口服咪唑斯汀缓释片皿治林后的药动学参数分别为:tmax为(1.70±0.59)h,cmax为(276.99±67.58)ng/mL,t1/2为(12.68±1.97)h,MRT为(15.29±2.67)h,AUC0→t为(2 555.89±777.52)ng/mL·h,AUC0→∞为(2 724.07±852.60)ng/mL·h;单剂量口服参比制剂尼乐后的药动学参数分别为:tmax为(1.95±0.64)h,cmax为(344.56±93.96)ng/mL,t1/2为(12.42±1.89)h,MRT为(13.49±1.60)h,AUC0→t为(2 532.28±776.06)ng/mL·h,AUC0→∞为(2 659.16±818.06)ng/mL·h.统计结果表明药动学参数t1/2、MRT、tmax、AUC0→T、AUC0→∞受试制剂皿治林与参比制剂尼乐相比没有显著性差异,cmax具有显著性差异,与参比制剂cmax相比有所降低.AUC0→t、AUC0→∞、cmax、t1/2和MRT生物等效,tmax生物不等效.受试制剂的相对生物利用度平均为(101.26±9.82)%(n=10,以AUC0→t计算)和(102.52±8.61)%(n=10,以AUC0→∞计算);药动学参数cmax的比值为(82.17±15.32)%.结论 受试制剂皿治林与参比制剂尼乐二者生物等效,但皿治林制剂咪唑斯汀峰浓度略低,达峰时间tmax略短.%Purpose The aim of this study was to compare the pharmacokinetic(PK) profile and relative bioavailability of two sustained release tablets containing 10 mg mizolastine in healthy, young Chinese volunteers. Methods A single oral dose of mizolastine was given under fasting conditions to volunteers aged from 21 to 24 years in this open-label, randomized, crossover study. A ten-day washout period was applied between each of the two formulations. Plasma samples were obtained before dosing and at predetermined time points after dosing up to 48 hours and were analyzed for plasma concentration with a high-performance-liquid chromatography-UV method. PK parameters representing the extent and the rate of absorption of mizolastine were obtained. An analysis of variance, 90% confidence intervals, and two one-sided tests were employed for statistical analysis of relative difference between the two formulations. Results According to the pharmacokinetic and statistical analysis, parameters were not statistically different between the two formulations except the peak concentration (cmax). The point estimates of the ratios of AUC0→t, AUC0→∞ of mizolastine were (101.26 + 9.82) % and (102.52 + 8.61)% with 90% confidence intervals (CIs) of 95. 5% - 106. 5% and 97. 7% -106.9% respectively, comprised in the stipulated 80% - 125% range; for cmax values, the ratios was 82.17% - 15.32% with the 90% CIs of 71. 7% - 91.1%, fell in the recommended range of 70% -143%. Conclusions The results indicate that there is no statistically significant difference in PK parameters except cmax between the two sustained release tablets of mizolastine. The 90% CIs of AUC0→t,AUC0→∞ and cmax are within the predefined range. Thus, the two sustained release tablets of mizolastine are considered bioequivalent and generally well tolerated.