Pharmacokinetic and pharmacodynamic drug–drug interactions between evogliptin and empagliflozin or dapagliflozin in healthy male volunteers

Abstract

Evogliptin (EV) is a novel dipeptidyl peptidase‐4 inhibitor (DPP4i) for glycemic control in patients with type 2 diabetes mellitus (T2DM). This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between EV and sodium glucose cotransporter‐2 inhibitors (SGLT2i) in healthy volunteers since combination therapy of DPP4i and SGLT2i has been considered as an effective option for T2DM treatment. A randomized, open‐label, multiple‐dose, two‐arm, three‐period, three treatments, two‐sequence crossover study was conducted in healthy Korean volunteers. In arm 1, subjects were administered 5 mg of EV once daily for 7 days, 25 mg of empagliflozin (EP) once daily for 5 days, and the combination once daily for 5 days (EV + EP). In arm 2, subjects were administered 5 mg of EV once daily for 7 days, 10 mg of dapagliflozin (DP) once daily for 5 days, and the combination once daily for 5 days (EV + DP). Serial blood samples were collected for PK analysis, and oral glucose tolerance tests were conducted for PD analysis. In each arm, a total of 18 subjects completed the study. All adverse events (AEs) were mild with no serious AEs. The geometric mean ratio and confidence interval of the main PK parameters (maximum concentration of the drug in plasma at steady state and area under the plasma drug concentration‐time curve within a dosing interval at a steady state) between EV and either EP or DP alone were not significantly altered by co‐administration. Administration of EV + EP or EV + DP did not result in significant PD changes, as determined by the glucose‐lowering effect. Administration of EV + EP or EV + DP had no significant effects on the PK profiles of each drug. All treatments were well‐tolerated.

SGLT2 inhibitors activate pantothenate kinase in the human heart

“…Treatment of purified PANK1 with EMPA activated pantothenate kinase activity to a similar extent as a previously described pan-PANK activator (PZ-2891 22 ) (Figure 3E and Supplementary Figure 2). Activation was achieved with a EC50 of 13 nM (Figure 3E), well below plasma concentrations achieved with EMPA therapy in humans (peak 500-1500 nM [14][15][16] ), and comparable to PZ-2891. We conclude that EMPA, at physiologically relevant concentrations, binds to and activates enzymatic activity of PANK1.…”

“…Tissue blocks were perfused with a recirculating Krebs-Henseleit buffer containing cardiac fuels at physiological concentrations, several of which were labeled with stable heavy isotopes ([6,6-2 H]-glucose, [1- 13 C]-glutamine, [3- 13 C]-lactate, [U- 13 C]valine, and [U- 13 C]-3-hydroxybutyrate) and then treated with either 700nM of the SGLT2i empagliflozin (EMPA) or vehicle control (Figure 1A). The chosen EMPA dose reflects plasma levels achieved in treated patients [14][15][16] . Multiple IVS blocks from each heart were cannulated and perfused in parallel such that every heart served as its own control.…”