Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor

Abstract

Empagliflozin is an orally active, potent and selective inhibitor of sodium glucose co-transporter 2 (SGLT2), currently in clinical development to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM). SGLT2 inhibitors, including empagliflozin, are the first pharmacological class of antidiabetes agents to target the kidney in order to remove excess glucose from the body and, thus, offer new options for T2DM management. SGLT2 inhibitors exert their effects independently of insulin. Following single and multiple oral doses (0.5-800 mg), empagliflozin was rapidly absorbed and reached peak plasma concentrations after approximately 1.33-3.0 h, before showing a biphasic decline. The mean terminal half-life ranged from 5.6 to 13.1 h in single rising-dose studies, and from 10.3 to 18.8 h in multiple-dose studies. Following multiple oral doses, increases in exposure were dose-proportional and trough concentrations remained constant after day 6, indicating a steady state had been reached. Oral clearance at steady state was similar to corresponding single-dose values, suggesting linear pharmacokinetics with respect to time. No clinically relevant alterations in pharmacokinetics were observed in mild to severe hepatic impairment, or in mild to severe renal impairment and end-stage renal disease. Clinical studies did not reveal any relevant drug-drug interactions with several other drugs commonly prescribed to patients with T2DM, including warfarin. Urinary glucose excretion (UGE) rates were higher with empagliflozin versus placebo and increased with dose, but no relevant impact on 24-h urine volume was observed. Increased UGE resulted in proportional reductions in fasting plasma glucose and mean daily glucose concentrations.

Fig. 1

Structural formula of empagliflozin

Fig. 2

Clinical pharmacokinetic and pharmacodynamic properties of empagliflozin in healthy volunteers. Results are expressed as means (± standard deviation for AUC_∞) (adapted from Seman et al. [19]). Increases in exposure (AUC_∞) (upper panel) in healthy subjects were dose-proportional over the range of empagliflozin doses used in this single rising-dose study. With the exception of the 200 mg dose, the amount of UGE_0–24h (lower panel) increased with increasing dose of empagliflozin, and maximum UGE (90.8 g) occurred at the 400 mg dose. AUC_∞ area under concentration–time curve of analyte in plasma over time interval from 0 h extrapolated to infinity, UGE_0–24h urinary glucose excretion over 24 h

Fig. 3

Clinical pharmacokinetic and pharmacodynamic properties of empagliflozin in patients with T2DM. Results are expressed as means (adapted from Heise et al. [23]). Increases in empagliflozin exposure (AUC_24h) in patients with T2DM were dose-proportional following multiple oral doses. UGE increased in empagliflozin dose groups at day 1 and this was maintained after multiple doses; however, almost no change was observed in the placebo group. MDG decreased on day 1 versus placebo, and dropped further by day 27. AUC_24h area under concentration–time curve of analyte in plasma over 24 h, MDG mean daily glucose, T2DM type 2 diabetes mellitus, UGE_0–24h urinary glucose excretion over 24 h