Pharmacokinetic comparison between fixed-dose combination and loose combination of enavogliflozin 0.3 mg and metformin HCl 1000 mg in healthy subjects under fasting and fed conditions

Abstract

Enavogliflozin is a sodium‒glucose cotransporter 2 inhibitor that can be administered in combination with metformin in patients with type 2 diabetes mellitus. This study aimed to compare the pharmacokinetics (PKs) between the fixed-dose combination (FDC) and the corresponding loose combination of enavogliflozin 0.3 mg and metformin 1000 mg. A randomized, open-label, 2-sequence, 4-period crossover study with a single oral dose was conducted in healthy subjects. Subjects received either the FDC or the corresponding loose combination of enavogliflozin 0.3 mg and metformin hydrochloride (HCl) 1000 mg in fasting and fed states. Serial blood samples were collected up to 72 h post-dose. Forty-four subjects were enrolled, and 37 subjects completed the study. In the fasting state, the geometric mean ratios (GMRs) (90% confidential interval (CI)) of the maximum plasma concentration (C_max) and the area under the concentration-time curve from time zero to the last quantifiable concentration (AUC_last) of the FDC to those of the corresponding loose combination were 1.03 (0.97-1.10) and 1.08 (1.03-1.13), respectively. The GMRs (90% CI) of the metformin C_max and AUC_last of the FDC to those of the corresponding loose combination were 1.10 (1.01-1.19) and 1.05 (1.00-1.11), respectively. In a high-fat-fed state, the GMRs (90% CI) of the enavogliflozin C_max and AUC_last of the FDC to those of the corresponding loose combination were 0.88 (0.82-0.93) and 1.03 (0.98-1.09), respectively. The GMRs (90% CI) of the metformin C_max and AUC_last of the FDC to those of the corresponding loose combination were 1.01 (0.98-1.05) and 1.00 (0.97-1.04), respectively. All the results were within the conventional bioequivalence range (0.80-1.25). There were no deaths, serious adverse events in fasting high-fat-fed states. The FDC of enavogliflozin 0.3 mg and metformin HCl and the corresponding loose combination were pharmacokinetically equivalent without safety concerns in fasting and high-fat-fed states. The FDC can be an alternative option for combination therapy with enavogliflozin and metformin HCl with improved compliance.

Keywords: Enavogliflozin; Extended-release tablet; Fixed-dose combination; Metformin; Pharmacokinetics.