依折麦布阿托伐他汀钙片在中国健康受试者中的生物等效性研究OA

Objective To evaluate the bioequivalence and safety profile of ezetimibe and atorvastatin calcium tablets(10 mg/10 mg)in healthy subjects.Methods This study utilized a single-center,randomized,open-label,four-period replicate crossover design.A total of 36 participants were enrolled for both fasting and fed state evaluations.Subjects,following a randomization plan,were administered orally either a single tablet of the test(T)or reference(R)formulation on the designated dosing day of each period.An 8-day washout interval separated treatment periods.Quantification of plasma levels for free ezetimibe,total ezetimibe(sum of free ezetimibe and its glucuronide conjugates)and atorvastatin were performed employing validated high-performance liquid chromatography-tandem mass spectrometry(LC-MS/MS).The pharmacokinetic parameters were analyzed using Phoenix WinNonlin 8.2 software,and the bioequivalence evaluation was conducted.Results Fasting state was as following:pharmacokinetic metrics Cmax of ezetimibe for T and R formulations were(6.35±3.22)and(7.04±3.20)ng·mL-1;AUC0-t were(107.10±46.61)and(109.67±50.23)ng·h·mL-1;AUC0-∞ were(114.88±49.96)and(117.14±50.74)ng·h·mL-1.The 90％confidence intervals for the geometric mean ratio of Cmax,AUC0-t and AUC0-∞ were 84.11％-98.34％,94.60％-106.44％and 93.52％-105.82％,respectively,all in the range of 80.00％-125.00％.Pharmacokinetic metrics Cmax of total ezetimibe for T and R formulations were(67.01±35.70)and(71.82±30.91)ng·mL-1;AUC0-t were(605.29±255.51)and(615.90±270.21)ng·h·mL-1;AUC0-∞ were(655.81±268.02)and(676.04±279.18)ng·h·mL-1.The 90％confidence intervals for the geometric mean ratio of Cmax,AUC0-t and AUC0-∞ were 85.32％-97.52％,92.35％-103.46％and 91.43％-102.13％,all in the range of 80.00％-125.00％.Pharmacokinetic metrics Cmax of atorvastatin for T and R formulations were(4.28±2.50)and(4.06±2.40)ng·mL-1;AUC0-t were(24.24±18.91)and(22.12±10.80)ng·h·mL-1;AUC0-∞ were(23.86±12.05)and(23.44±10.98)ng·h·mL-1.The individual coefficient of variation for Cmax with the one-sided 95％upper confidence limit below the zero boundary value.The geometric mean ratio for Cmax was 1.06,falling within the acceptance range 0.80-1.25.The 90％confidence intervals for the geometric mean ratiosof AUC0-t and AUC0-∞ were 97.11％-109.14％and 97.24％-104.00％,all in the range of 80.00％-125.00％.The pharmacokinetic parameters of active ingredients in the fed group were as follows:for ezetimibe,the Cmax values of the test and reference preparations were(12.50±8.43)and(12.10±10.20)ng·mL-1,respectively;the AUC0-t values were(115.66±61.86)and(114.91±61.10)ng·h·mL-1,respectively;and the AUC0-∞ values were(127.40±66.49)and(128.37±66.73)ng·h·mL-1,respectively.The one-sided 95％upper confidence limit for ezetimibe Cmax was＜0,with a GMR of 1.09,within the range of 0.80-1.25.The 90％confidence intervals for the geometric mean ratios of AUC0-t and AUC0-∞ were 93.63％-107.27％and 91.07％-108.13％,respectively,both within 80.00％-125.00％.For total ezetimibe,the Cmax values of the test and reference preparations were(102.02±50.21)and(95.10±48.31)ng·mL-1,respectively;the AUC0-t values were(660.62±342.67)and(645.43±290.84)ng·h·mL-1,respectively;the AUC0-∞ values were(728.80±356.15)and(711.88±301.04)ng·h·mL-1,respectively.The one-sided 95％upper confidence limit for total ezetimibe Cmax was＜0,with a GMR of 1.08,within the range of 0.80-1.25.The 90％confidence intervals for the geometric mean ratios of AUC0-t and AUC0-∞ were 95.12％-106.95％and 95.27％-107.60％,respectively,both within 80.00％-125.00％.For atorvastatin,the Cmax values of the test and reference preparations were(1.79±0.80)and(1.83±0.87)ng·mL-1,respectively;the AUC0-tvalues were(19.09±6.85)and(18.24±6.29)ng·h·mL-1,respectively;and the AUC0-∞ values were(21.25±6.97)and(20.34±6.84)ng·h·mL-1,respectively.The 90％confidence intervals for the geometric mean ratios of Cmax,AUC0-t and AUC0-∞ were 91.25％-106.96％,99.81％-108.09％and 100.22％-108.73％,respectively,all falling within the range of 80.00％-125.00％.Conclusion The test formulation of ezetimibe and atorvastatin calcium tablets met bioequivalence criteria relative to the reference product in healthy subjects under both fasting and fed(high-fat meal)conditions.