阿奇霉素片人体相对生物利用度和生物等效性试验研究

【作者】 孙鹏；

【导师】 金英顺；

【作者基本信息】 延边大学 ， 药理学， 2007， 硕士

【摘要】 生物利用度是保证药品内在质量的重要指标，生物等效性是保证含同一药物的不同制剂质量一致性的主要依据，建立生物样品中药物的灵敏和特异的分析方法是进行该项研究的基础。本文应用抗生素微生物检定法（管碟法）建立了测定人血浆中阿奇霉素浓度的分析方法，并应用于阿奇霉素片人体相对生物利用度和生物等效性试验研究。建立了灵敏、专属的抗生素微生物检定法测定人血浆中阿奇霉素的浓度。阿奇霉素的线性范围为0.0048～0.8546μg／ml，定量下限为0.0048μg／ml，日内、日间精密度（RSD％）小于15％，准确度（加样回收率）在85％～115％范围内。本文采用上述的分析方法，对两种品牌的阿奇霉素片在健康男性志愿者中进行了单次口服相对生物利用度和生物等效性试验研究。采用双周期两制剂交叉试验设计，19名健康男性志愿者分别单次口服给药500mg受试制剂和参比制剂。洗净期为2周。服药后，采集144h内系列血样，用抗生素微生物检定法测定血药浓度。根据血药浓度确定主要的药物动力学参数AUC_0-24h、AUC_0-、C_max、t_max和t_1／2。结果显示受试制剂和参比制剂的t_1／2分别为34.61±7.419h和31.16±5.28h，C_max分别为557.15±129.57μg／L和548.34±137.61μg／L，t_max分别为2.605±0.209h和2.550±0.16h，AUC_0-24h分别为8452.1±2286.1μg·h／L和8665.0±2343.7μg·h／L，AUC_0-分别为8860.6±2359.8μg·h／L和9009.5±2492.2μg·h／L。以AUC_0-24h计算的相对生物利用度为99.0±20.4％；以AUC_0-计算的相对生物利用度为100.0±19.0％。将AUC_0～24和C_max数据经对数转换后进行生物等效性评价。经方差分析和双单侧t检验发现差异无显著意义。受试制剂AUC_0～24h的90％可信限落在参比制剂的80％～125％范围内，C_max的90％可信限落在参比制剂的70％～143％范围内。根据统计学分析，本文得出结论认为受试制剂和参比制剂生物等效。更多还原

【Abstract】 Bioavailability is a crucial indicator to ensure the quality of drug while bioequivalence serves as an important base on which the quality of different preparations within the same drug are ensured to be identical. The basis of this study is to develop a sensitive and specific analytical method for the determination of azithromycin in human biological samples. One microbiological assay method (Cylinder-plate method) for the determination of azithromycin in human plasma was developed and validated and was used in the relative bioavailability and bioequivalence study of azithromycin.A sensitive and specific, microbiological assay has been developed and validated for the determination of azithromycin in human plasma. The assay was reproducible and linear for azithromycin in the range of 0.0048～0.8546μg/ml. The lower limit of quantification of azithromycin was 0.0048μg/ml. The intra-day and inter-day precision (expressed as RSD%) was less or equal to 15% and accuracy (added quantities recovery) was within 85%～115%.The single oral dose relative bioavailability and bioequivalence study of two bands of azithromycin tablets was studied in healthy male volunteers by the above validated microbiological assay.A single oral dose of 500 mg of test preparation and reference preparation of azithromycin was administered to 19 healthy man volunteers, respectively, in a randomized, two-period cross-over design. The washout period was two weeks.After dosing, serial blood samples were collected for a period of 144 h. Plasma concentrations of azithromycin were analyzed using microbiological assay. Pharmacokinetic parameters including AUC0-24h, AUCo, Cmax, tmax, and t1/2 were determined.The results showed that t1/2 were 34.61±7.419h and 31.16±5.28h, Cmax were 557.15±12957μg/L and 548.34±137.61μg/L, tmax were 2.605±0.209 h and 2.550±0.16 h, AUC0-24h were 8452.1±2286.1μg-h/L and 8665.0±2343.7μg·h/L, AUCo were 8860.6±2359.8μg.h/L and 9009.5+±492.2μg·h/L following oral administration of test and reference preparation, respectively. The relative bioavailability and bioequivalence of AUCo-24h was 99.0±20.4%, the relative bioavailability and bioequivalence of AUCo was 100.0±19.0%.AUCo-24hand Cmaxwere tested for bioequivalence after log-transformation of data. No significant difference was found based on analysis of variance and two one side t-test of significance. 90% confidence intervals for test preparation / reference preparation ratios of AUCo-24h were found within the bioequivalence acceptance range of 80-125%. 90% confidence intervals for test preparation / reference preparation ratios of Cmax were found within the bioequivalence acceptance range of 70-143%. Based on the above statistical results, it was concluded that the test preparation is bioequivalent to the reference preparation.更多还原