辛伐他汀片空腹和餐后给药人体生物等效性研究

Bioequivalence study of simvastatin tablets in healthy Chinese volunteers

目的:评价中国健康受试者空腹和餐后口服辛伐他汀片后,辛伐他汀和代谢物辛伐他汀酸的人体生物等效性。方法:本研究包括空腹和餐后给药的2个试验,均为随机、开放、两制剂、三序列、三周期、部分重复交叉设计的生物等效性试验。空腹和餐后各入组42名健康受试者,分成3组,每组受试者分别交叉口服20 mg辛伐他汀片的受试制剂1次和参比制剂2次。采用液相色谱-串联质谱(LC-MS/MS)法检测给药后血浆中辛伐他汀及其代谢物辛伐他汀酸的浓度。结果:在评价2种制剂的生物等效性时,当药动学参数(Cmax,AUC0~t,AUC0~∞)的个体内标准差SWR<0.294时,以平均生物等效性评价方法(ABE)进行评价;SWR≥0.294时,则以参比制剂标度的平均生物等效性方法(RSABE)进行评价。空腹给药后,参比制剂辛伐他汀的AUC0~t和AUC0~∞的个体内标准差SWR分别为0.323和0.318,(YT-YR)^2-θs^2 WR的95%置信区间上限分别为-0.005和-0.0103,且受试制剂与参比制剂的几何均值比(T/R)分别为118.41%和116.70%;参比制剂辛伐他汀Cmax的个体内标准差SWR为0.255,受试与参比的几何均值数比值(T/R)及其90%置信区间为103.42%(95.30%~112.23%)。代谢物辛伐他汀酸的各参数的个体内标准差SWR均<0.294,AUC0~t,AUC0~∞,Cmax的几何均值比值(T/R)及其90%置信区间分别为112.82%(105.99%~120.08%),111.86%(105.11%~119.04%),115.05%(107.57%~123.05%)。高脂餐给药后,参比制剂辛伐他汀的Cmax的个体内标准差SWR为0.349,(YT-YR)^2-θs^2 WR的95%置信区间上限为-0.0341,受试制剂与参比制剂Cmax几何均值比值为87.12%;参比制剂辛伐他汀的AUC0~t及AUC0~∞的个体内标准差SWR均<0.294,几何均值数比值(T/R)及其90%置信区间分别为95.73%(89.63%~102.25%)和95.92%(89.90%~102.34%)。代谢物辛伐他汀酸的Cmax,AUC0~t,AUC0~∞的个体内标准差SWR均>0.294,这些参数的(YT-YR)^2-θs^2 WR的95%置信区间上限均<0,且几何均值比均在80.00%~125.00%。结论:在空腹和餐后条件下,受试制剂与参比制剂辛伐他汀和代谢物辛伐他汀酸的药动学评价指标具有生物等效性。

Objective:To evaluate the bioequivalence of two formulations of 20 mg simvastatin tablets in healthy Chinese subjects under fast and fed conditions.Methods:This was a randomized,open-label,two formulations,3-sequence,3-periods,partial-replicated study in healthy Chinese subjects under fast and fed conditions.42 healthy subjects were divided into the fast and fed groups.Each subject was administered with test formulation one time and reference formulation 2 times.Simvastatin and its metabolite simvastatin hydroxy acid in plasma were measured by a validated liquid chromatography-tandem mass spectrometry(LC-MS/MS)method.Results:For evaluating the bioequivalence of the two formulations,when the intra-subject standard deviation SWR of the pharmacokinetic parameters(Cmax,AUC0-t,AUC0-∞)was less than 0.294,the average bioequivalence evaluation method(ABE)was used,while when SWR≥0.294,the reference-scaled average bioequivalence(RSABE)was used.After administration in fasting condition,the SWR(s)of AUC0-t and AUC0-∞for reference simvastatin preparation were 0.323 and 0.318,respectively,the upper 95%confidence intervals of(Y^-T-Y^-R)^2-θs^2 WR,respectively,and the geometric mean ratios(T/R)were 118.41%and 116.70%,respectively.The SWR of Cmax for reference simvastatin preparation was 0.255,the geometric mean ratio(T/R)and its 90%confidence interval were 103.42%and 95.30%~112.23%.The SWR(s)of Cmax,AUC0-t,and AUC0-∞of simvastatin hydroxy acid were all<0.294,the geometric mean ratios(T/R)and 90%confidence intervals were 112.82%(105.99%~120.08%),111.86%(105.11%~119.04%),and 115.05%(107.57%~123.05%),respectively.After administration in fed condition,the SWR of Cmax for reference simvastatin preparation was 0.349,the upper 95%confidence interval of was-0.0341,the geometric mean ratio(T/R)was 87.12%.The SWR(s)of AUC0-t and AUC0-∞for reference simvastatin preparation were<0.294,the geometric mean ratio(T/R)was 95.73%(89.63%~102.25%)and 95.92%(89.90%~102.34%),respectively.The SWR(s)of Cmax,AUC0-t,and AUC0-∞of simvastatin hydroxy acid were>0.294,the upper 95%confidence intervals of(Y^-T-Y^-R)^2-θs^2 WR were all<0,and the geometric mean ratio(T/R)was within 80.00%~125.00%.Conclusion:The test and reference simvastatin formulations are bioequivalent under fast and fed conditions.