Pharmacokinetic and pharmacodynamic interaction of enavogliflozin, a sodium-glucose cotransporter 2 inhibitor, with glimepiride and metformin in healthy participants.

Abstract

Aims: Enavogliflozin, a sodium-glucose cotransporter 2 inhibitor, is expected to be coadministered with antihyperglycaemic drugs with different mechanisms of action. This study aimed to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between enavogliflozin, glimepiride and metformin.

Methods: A randomized, open-label, two-sequence, three-period crossover study was conducted. Participants received one of the following three treatments for 6 days in each period: enavogliflozin 0.3 mg once daily (E), glimepiride 2 mg once daily and metformin 1000 mg twice daily combination (GM) or the combination of all three study drugs (E + GM). Serial blood and urine samples were collected for PK and PD assessments at steady state.

Results: The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum plasma concentration (C_max,ss) of enavogliflozin, glimepiride and metformin were 1.0811 (1.0273-1.1378), 1.1495 (1.0602-1.2464) and 1.0556 (0.9937-1.1215), respectively. The corresponding values for the area under the plasma concentration-time curve within a dosing interval (AUC_τ,ss) were 1.0031 (0.9541-1.0545), 1.2264 (1.1383-1.3213) and 1.1638 (1.0958-1.2361) respectively. A 24-h urinary glucose excretion (UGE_0-24h) induced by E was affected by coadministration of GM, with the GMR (90% CI) of 0.7834 (0.7307-0.8400). Serum glucose reduction was greatest with the E + GM, followed by GM, and then E.

Conclusions: No clinically meaningful PK interaction of enavogliflozin, glimepiride and metformin was observed. Although a reduction in UGE_0-24h was observed, an additive PD interaction was observed in serum glucose levels. The results suggest that enavogliflozin can be coadministered with glimepiride and metformin without requiring dose adjustments of either of these drugs.