To evaluate the bioequivalence and safety profile of ezetimibe and atorvastatin calcium tablets (10 mg/10 mg) in healthy subjects.

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.

Fasting state was as following: pharmacokinetic metrics C_max of ezetimibe for T and R formulations were (6.35±3.22) and (7.04±3.20) ng·mL^-1; AUC_0-t were (107.10±46.61) and (109.67±50.23) ng·h·mL^-1; AUC_0-∞ were (114.88±49.96) and (117.14±50.74) ng·h·mL^-1. The 90% confidence intervals for the geometric mean ratio of C_max, AUC_0-t and AUC_0-∞ 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 C_max of total ezetimibe for T and R formulations were (67.01±35.70) and (71.82±30.91) ng·mL^-1; AUC_0-t were (605.29±255.51) and (615.90±270.21) ng·h·mL^-1; AUC_0-∞ were (655.81±268.02) and (676.04±279.18) ng·h·mL^-1. The 90% confidence intervals for the geometric mean ratio of C_max, AUC_0-t and AUC_0-∞ 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 C_max of atorvastatin for T and R formulations were (4.28±2.50) and (4.06±2.40) ng·mL^-1; AUC_0-t were (24.24±18.91) and (22.12±10.80) ng·h·mL^-1; AUC_0-∞were (23.86±12.05) and (23.44±10.98) ng·h·mL^-1. The individual coefficient of variation for C_max with the one-sided 95% upper confidence limit below the zero boundary value. The geometric mean ratio for C_max was 1.06, falling within the acceptance range 0.80-1.25. The 90% confidence intervals for the geometric mean ratios of AUC_0-t and AUC_0-∞ 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 C_max values of the test and reference preparations were (12.50±8.43) and (12.10±10.20) ng·mL^-1, respectively; the AUC_0-t values were (115.66±61.86) and (114.91±61.10) ng·h·mL^-1, respectively; and the AUC_0-∞ 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 C_max 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 AUC_0-t and AUC_0-∞ were 93.63%-107.27% and 91.07%-108.13%, respectively, both within 80.00%-125.00%. For total ezetimibe, the C_max values of the test and reference preparations were (102.02±50.21) and (95.10±48.31) ng·mL^-1, respectively; the AUC_0-t values were (660.62±342.67) and (645.43±290.84) ng·h·mL^-1, respectively; the AUC_0-∞ 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 C_max 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 AUC_0-t and AUC_0-∞ were 95.12%-106.95% and 95.27%-107.60%, respectively, both within 80.00%-125.00%. For atorvastatin, the C_max values of the test and reference preparations were (1.79±0.80) and (1.83±0.87) ng·mL^-1, respectively; the AUC_0-t values were (19.09±6.85) and (18.24±6.29) ng·h·mL^-1, respectively; and the AUC_0-∞ 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 C_max, AUC_0-t and AUC_0-∞ 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%.

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.