非布司他片在中国健康受试者中单次和多次口服给药的药代动力学研究

Pharmacokinetics study of single and multiple doses of febuxostat in Chinese healthy subjects

目的评价单次和多次口服非布司他片在中国健康受试者中的药代动力学特征以及安全性。方法本研究共纳入24例健康受试者,单次给药试验12例,多次给药试验12例。单次给药试验采用随机、自身对照、三剂量水平三周期交叉设计,分为3组,每组4例,依据周期先后分别服用非布司他片20,40,80 mg,每1周期用药1次。另入选12例受试者进行40 mg剂量的多次给药试验。试验第1天口服40 mg,第3天继续服用40 mg,每日1次,并连续给药6次至第8天。单次给药和多次给药试验均按计划的采血时间点采集静脉血,通过高效液相串联质谱法检测受试者血浆样本中非布司他的浓度。绘制药时曲线,用WinNonlin8.0软件进行药代动力学参数计算和分析。结果单次给药试验3个组的AUC_(0-t)分别为(2.52±1.09)×10^(3)、(5.82±1.83)×10^(3)和(13.61±5.02)×10^(3)ng·h·mL^(-1);Cmax分别为(1.10±0.48)×10^(3)、(2.34±0.62)×10^(3)和(4.31±1.54)×10^(3)ng·mL^(-1)。多次口服非布司他片试验第1天非布司他的药代动力学参数,AUC_(0-24h)为(6.49±2.04)×10^(3)ng·h·mL^(-1),C_(max)为(2.31±0.78)×10^(3)ng·mL^(-1)。多次口服非布司他片后,试验第8天非布司他的药代动力学参数,AUC_(0-∞)为(6.65±2.21)×10^(3)ng·h·mL^(-1),AUC_(0-24 h)为(6.28±2.11)×10^(3)ng·h·mL^(-1),C_(ss_max)为(1.89±0.82)×10^(3)ng·h·mL^(-1)。结论单、多次口服给药后,非布司他20~80 mg在人体内的药代动力学过程基本符合线性特征,建议非布司他片在Ⅱ、Ⅲ期临床试验等的单次口服给药剂量范围20~80 mg,多次口服给药剂量为40 mg,给药间隔为24 h。

Objective To evaluate the pharmacokinetic characteristics and safety of single and multiple oral febuxostat tablets in Chinese healthy subjects.Methods A total of 24 healthy subjects were enrolled in this study,including 12 cases of single administration and 12 cases of multiple administration.The single-dose trial was a randomized,selfcontrolled,three-dose level,three-cycle crossover design.The subjects were divided into 3 groups,4 cases in each group.According to the cycle,three different doses of febuxostat tablets were given,namely low(20 mg),medium(40 mg)and high(80 mg),once per cycle.Another 12 subjects were enrolled for multiple dosing at a dose of 40 mg.On the first day of the experiment,40 mg was taken orally,and on the third day,40 mg was continued to be taken,once a day,for 6 consecutive times to the eighth day,and the time of each administration was as consistent as possible.The concentration of febuxostat in plasma samples was determined by high performance liquid tandem mass spectrometry.PKparameters were calculated and analyzed by Win Nonlin 8.0 software.Results The AUC_(0-t)of the three groups of the single drug administration test were(2.52±1.09)×10^(3),(5.82±1.83)×10^(3)and(13.61±5.02)×10^(3)ng·h·mL^(-1);the C_(max) were(1.10±0.48)×10^(3),(2.34±0.62)×10^(3)and(4.31±1.54)×10^(3)ng·mL^(-1),respectively.Pharmacokinetic parameters of febuxostat on day 1 of multiple oral febuxostat tablet test were as follows:AUC_(30-24h)was(6.49±2.04)×10ng·h·mL^(-1),Cmaxwas(2.31±0.78)×10^(3)ng·mL^(-1).After multiple oral doses of febuxostat tablets,the pharmacokinetic parameters of febuxostat on day 8 were as follows:AUC_(0-∞)was(6.65±2.21)×10^(3)ng·h·mL^(-1),AUC_(30-24h)was(6.28±2.11)×10^(3) ng·h·mL^(-1),C_(ss_max)was(1.89±0.82)×10^(3)ng·h·mL^(-1).Conclusion After single and multiple oral administration,the pharmacokinetics process of non-bulistat in the human body was basically linear in the range of 20-80 mg,which suggested that the single oral dose of febutamol in phaseⅡandⅢclinical trials should be 20-80 mg,and the multiple oral doses should be 40 mg,with an interval of 24 h.