伊拉地平胶囊在中国健康人体的药代动力学研究

Pharmacokinetic Study on Isradipine Capsule in Chinese Healthy Volunteers

目的：评价中国健康人单剂量口服伊拉地平胶囊后体内的药代动力学.方法：随机、开放、单中心Ⅰ期临床研究,9、12、9名健康男女受试者分别单剂量口服伊拉地平胶囊2.5、5、10mg,按方案设计时间点采集血浆样本,采用LC-MS/MS法测定血浆中伊拉地平浓度,并应用WinNonlin（R） 6.3软件对血药浓度数据进行处理,计算药动学参数.应用SPSS 18.0软件及置信区间方法评价伊拉地平单剂量给药的线性药代动力学特征.结果：受试者单剂量口服2.5、5、10mg伊拉地平后,平均Cmax.分别为（1 440.23±548.59）、（2 466.33±622.72）和（4 610.21±1 471.91） pg·mL-1,tmax分别为（1.30±0.65）、（1.04±0.53）和（1.46±0.42）h,t1/2分别为（10.47±2.32）、（13.22±4.38）和（11.65±4.38）h,AUC（0-t）分别为（9 663±3 463）、（13 878±3 571）和（33 500±11 084） pg·h·mL-1.置信区间法评价结果显示,2.5～10mg给药范围内伊拉地平的AUC（0-t）、AUC（0-∞）和Cmax的置信区间与判断区间部分重叠,伊拉地平是否具有线性药代动力学特征尚不能判断.结论：30名健康受试者单剂量口服伊拉地平胶囊,Cmax、AUC等参数随剂量升高而增大,但若θ值采用传统界值,则无法判断2.5～10mg给药范围内是否具有线性药代动力学特征;可见θ值的选择与线性评价结果密切相关,在新药早期探索性研究中是否应增大θ值范围值得研究者商榷.

Objective：To study the pharmacokinetic profiles of isradipine capsule with a single oral administration in Chinese healthy volunteers.Methods：Randomized,open,single-center phase Ⅰ clinical trial,9,12,9 healthy male and female subjects were given isradipine capsules orally at a single dose of 2.5mg,5mg and 10mg,respectively.Plasma samples were obtained at time points specified by protocol to characterize the pharmacokinetics of isradipine.The isradipine concentrations were determined by LC-MS/MS.The pharmacokinetic parameters were calculated by WinNonlin（R）6.3 and assessed by confidence interval model using SPSS18.0.Results：The pharmacokinetic parameters of the above doses were as follows：Cmax were （1 440.23±548.59）、（2 466.33±622.72） and （4 610.21 ±1 471.91） pg·mL-1,tmax were （1.30±0.65）、（1.04±0.53） and （1.46 ±0.42） h,t1/2 were （10.47±2.32） 、（13.22t4.38） and （11.65±4.38） h,AUC（0-t） were （9 663±3 463）、（13 878±3 571） and （33 500±11 084） pg·h·mL1. At the range of 2.5 ～10mg,the confidence intervals and the critical region of AUC（0-t）,AUC（0-∞）and Cmax overlapped,and dose-dependent kinetics was uncertain.Conclusion：30 healthy volunteers received single dose of isradipine capsules orally.C AUC and other parameters appeared to be dose dependent.However,if default values of θ were chosen,dose proportionality cannot be concluded at the above doses range.Therefore the values of θ are closely related with the assessment result,and alternative criterion for exploratory assessment for dose proportionality may be discussed and selected.