波生坦片在中国健康受试者中的生物等效性研究

目的:评价中国健康受试者单剂量口服波生坦片受试制剂和参比制剂的人体生物等效性。方法:采用随机、开放、双序列、双周期交叉设计，24例中国健康男性受试者，分别在空腹和餐后情况下，单剂量口服波生坦参比和受试制剂各125 mg。采用高效液相色谱-串联质谱法测定血浆中的波生坦及其活性代谢物羟基波生坦的浓度，以WinNonlin软件按非房室模型计算药代动力学参数，进行生物等效性评价。结果:空腹试验，受试和参比制剂波生坦主要药代动力学参数：Cmax分别为(2.72±1.09)、(2.59±1.02) μg/mL，AUC0-t分别为(13.51±4.55)、(12.61±4.25) μg·mL-1·h，AUC0-∞分别为(14.04±4.46)、 (13.02±4.24) μg·mL-1·h，tmax分别为(3.75±0.81)、(3.98±0.76) h，t1/2分别为(2.70±0.88)、(2.77±0.91) h。餐后试验受试和参比制剂波生坦主要药代动力学参数：Cmax分别为(2.84±0.68)、(2.95±0.99) μg/mL， AUC0-t分别为(14.66±4.27)、(15.34±6.09) μg·mL-1·h， AUC0-∞分别为(15.04±4.41)、(15.68±6.19) μg·mL-1·h，tmax分别为(3.98±1.05)、(3.98±1.21) h，t1/2分别为(2.55±0.65)、(2.71±0.63) h。空腹和餐后试验，两制剂波生坦的AUC0-t、AUC0-∞、Cmax经对数转换后行方差分析，两制剂在给药顺序、制剂间及周期间均无统计学差异(P＞0.05)。在α=0.05水平上行双单侧t检验，AUC0-t、AUC0-∞、Cmax的90%置信区间均在80%～125%的等效区间范围内。结论:波生坦片受试制剂与参比制剂在空腹和餐后条件下均具有生物等效性。

Bioequivalence of bosentan tablets in healthy Chinese volunteers

AIM: To evaluate the bioequivalence of a single oral dose of bosentan tablets of test and reference formulations in healthy Chinese volunteers. METHODS: It was a randomized, open-label, two sequences, two period crossover study. A single oral dose of 125 mg test and reference formulations were given to 24 healthy Chinese volunteers under fasting and fed conditions. The concentrations of bosentan and its active metabolite hydroxybosentan in plasma were determined by high performance liquid chromatography tandem mass spectrometry. The pharmacokinetic parameters were calculated and the bioequivalence was compared by non-compartment model of WinNonlin program. RESULTS:The bosentan's major pharmacokinetic parameters of test and reference under fasting condition were as follow: Cmax were (2.72±1.09) and (2.59±1.02) μg/mL, AUC0-t were (13.51±4.55) and (12.61±4.25) μg·mL-1·h, AUC0-∞ were (14.04±4.46) and (13.02±4.24) μg·mL-1·h, tmax were (3.75±0.81) and (3.98±0.76) h, t1/2 were (2.70±0.88) and (2.77±0.91) h。The bosentan's major pharmacokinetic parameters of test and reference under fed condition were as follow: Cmax were (2.84±0.68) and (2.95±0.99) μg/mL, AUC0-t were (14.66±4.27) and (15.34±6.09) μg·mL-1·h, AUC0-∞ were (15.04±4.41) and (15.68±6.19) μg·mL-1·h, tmax were (3.98±1.05) and (3.98±1.21) h, t1/2 were (2.55±0.65) and (2.71±0.63) h. There was no significant difference among the order of administration, formulations and cycles (P>0.05); The 90% confidence intervals of AUC0-t, AUC0-∞ and Cmax were in the range of 80%-125% by double-sided t test at the level of α=0.05.CONCLUSION: The two formulations of bosentan tablets were bioequivalent in Chinese healthy volunteers under fasting and fed condition.