Comparison of the Pharmacokinetics, Safety, and Tolerability of Two Empagliflozin Formulations in Healthy Korean Subjects

Abstract

Empagliflozin is a sodium-glucose cotransporter 2 inhibitor that is commonly used for the treatment of type 2 diabetes mellitus. As cocrystal formulation can improve the chemical properties of drugs, CKD-370 was newly developed as a cocrystal formulation of empagliflozin with solvate L-proline. This study aimed to compare the pharmacokinetics, safety, and tolerability of these two empagliflozin formulations in healthy Korean subjects. Methods: A randomized, open-label, two-sequence, two-period crossover study was conducted on healthy Korean participants. The subjects received a single oral 25 mg dose of either test (CKD-370) or reference treatment (Jardiance ® ) tablet at each period. Plasma empagliflozin concentrations were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic (PK) parameters were analyzed using non-compartmental methods. The primary PK parameters included the maximum concentration (C max ) and the area under the concentration-time curve from 0 to last (AUC last ). The safety of both formulations was monitored and evaluated. Results: A total of 28 healthy Korean adult subjects were randomized, and 27 subjects were included in the PK analysis. The mean ± standard deviation values of the primary PK parameters, C max and AUC last after administration of the test treatment, were 442.02 ± 103.37 μg/L and 3131.08 ± 529.30 μg•h/L, respectively, and those after administration of the reference treatment were 436.29 ± 118.74 μg/L and 3006.88 ± 514.21 μg•h/L, respectively. The geometric mean ratio and its 90% confidence interval of test to reference treatment for C max and AUC last were 1.0221 (0.9527-1.0967) and 1.0411 (1.0153-1.0677), respectively, which were within the commonly accepted bioequivalence criteria of 0.80 to 1.25. Both treatments were well-tolerated. Conclusion:The two formulations of empagliflozin showed similar PK characteristics and were generally well tolerated in healthy subjects.

A Population Pharmacokinetic Study to Compare a Novel Empagliflozin L-Proline Formulation with Its Conventional Formulation in Healthy Subjects

“…According to the PK results in the clinical studies, the maximum values of time to maximum plasma concentration (T max ) were the same; however, the minimum T max values of empagliflozin L-proline were larger than that of empagliflozin for two dose strengths, which meant that empagliflozin L-proline took more time to reach T max , and also reflected that breaking down L-proline in the digestive system requires time [ 25 , 26 ]. However, the results of the population PK analysis showed that formulation differences did not affect PK parameters as covariates, which suggested that the difference in the absorption phase is not significantly meaningful and can be ignored.…”

“…In the first study (NCT03849495), the study drugs used were 25 mg empagliflozin L-proline and the conventional 25 mg empagliflozin formulation [ 26 ]. In the second study (NCT03848637), the study drugs were fixed-dose combinations of 5 mg/1000 mg empagliflozin L-proline/metformin and 5 mg/1000 mg empagliflozin/metformin [ 25 ].…”

“…In the second study, the plasma concentrations of empagliflozin were quantified by using liquid chromatography–mass spectrometry (LC–MS) equipped with API 4000 (SCIEX; multiple reaction monitoring, electrospray ionization, and positive SCIEX mode). All experiments adhered to the standards of good laboratory practice as described previously [ 25 , 26 ]. The calibration ranges in these two studies were 2–1500 ng/mL and 0.5–150 ng/mL, respectively.…”

“…According to the preclinical studies, it was found that empagliflozin L-proline can be broken down to empagliflozin in the digestive system and be absorbed in the form of empagliflozin (data on file). Two comparative PK studies, one on CKD-370 and empagliflozin and another on CKD-370/metformin and empagliflozin/metformin fixed-dose combinations, were both conducted in 2019 [ 25 , 26 ]. The PK, safety, and tolerability of these two empagliflozin formulations were investigated through clinical studies.…”