4种市售尼莫地平口服片剂的相对生物利用度及生物等效性评价

Study of the bioequivalence of four formulations of nimodipine in healthy volunteers

目的:评价4种市售尼莫地平口服片剂的相对生物利用度和生物等效性。方法:选择12名健康受试者,采用随机交叉四组试验,分别口服120mg3种国产尼莫地平片(B,C,D)与德国拜尔药厂的尼莫通片(A)。血药浓度由本实验室改进的高效液相色谱法测得,按照PCNONLIN程序非房室模型型分析法获得个体生物利用度参数tmax,cmax和AUC0～∞。根据被测不同片剂间AUC0～∞之比得出相对生物利用度(F);并将AUC0～∞等参数对数转换,在方差分析基础上再行双单侧检验进行生物等效性评价。结果:A,B,C和D的tmax分别为(0.6±0.2),(1.1±1.2),(0.5±0.1),(0.5±0.2)h;cmax分别为(108.8±59.5),(56.1±30.7),(73.2±34.9),(94.7±41.1)ng·ml-1;AUC0～∞分别为(175.4±77.9),(135.8±62.4),(154.8±69.5),(1545±51.6)ng·h·ml-1。B,C和D对于A的相对生物利用度分别为83.7%,93.1%,97.6%,90%置信区间结果显示,B,C和DAUC0～∞平均值分别为A的66.7%～88.8%,77.2%～102.7%和80.5%～107.1%,D与A具有生物等效性。

OBJECTIVE: The objective was to compare the bioavailability and bioequivalence of four generic marketing formulations. METHODS: The study design was a single dose, randomized fou way crossover with a 1 week washout period between each phase of the experiment dosing. Plasma concentration time profiles were determined and the bioavailabilities of different formulations of nimodipine tablets (A,B, C and D )following oral administration of a 120mg nimodipine single dose were compared.RESULTS:The t max of the tablet A, B, C and D was (0.6 ± 0.2) , (1.1 ± 1.2), (0.5 ± 0.1) and (0.5 ± 0.2) h, respectively; the c max was (108.8 ± 59.5), (56.1 ± 30.7), (73.2±34.9) and (94.7 ± 41.1) ng·ml -1 , respectively; and the AUC was (175.4 ± 77.9) , (135.8 ±62.4 ), (154.8 ± 69.5) and (154.5 ± 51.6)ng·h·ml -1 , respectively. The relative bioavailabilities of tablet B, C and D compared with tablet A were 83.7%, 93.1% and 97.6%, respectively. The 90% confidence interval for the AUC shown for tablet B and C were 66.7～88.8% and 77.2～102.7%, respectively, less than 80% compared to the reference at the low range estimate; tablet D was 80.5～107.1%, greater than 80% compared to the reference at the low range estimate. CONCLUSION: The 90% confidence interval with respect to AUC was between 80% and 125%, the formulation B and C were not considered bioequivalent, formulation D was considerded bioequivalent,compared with formulation A.