Single‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Volunteers and Patients With Type 2 Diabetes Mellitus

Abstract

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5-500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at approximately 30 to 45 minutes postdose (t(max)), and had a plasma elimination half-life (t(1/2)) of approximately 0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose-related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings.

Ipragliflozin (ASP1941), a selective sodium-dependent glucose cotransporter 2 inhibitor, safely stimulates urinary glucose excretion without inducing hypoglycemia in healthy Japanese subjects

“…In agreement with the European phase 1 ipragliflozin study [21], as well as studies of other SGLT2 inhibitors [23][24][25], ipragliflozin administration did not cause any significant changes in blood glucose levels in healthy subjects compared with placebo. Kolodny et al [26] showed that infusion of phlorizin, a natural inhibitor of SGLT1 and SGLT2, induced hepatic glucose output without significant changes in the plasma glucose concentration in the portal vein in normal dogs, while urinary glucose was increased promptly after its treatment.…”

Usefulness of a novel system for measuring glucose area under the curve while screening for glucose intolerance in outpatients

“…Changes in PG AUC are used to evaluate the efficacy of medicines such as a-glucosidase inhibitors or nateglinide for postprandial hyperglycemia 18,19 . This trend is also apparent in the evaluation of recently developed medicines, such as incretin-related agents and sodium-glucose cotransporter type 2 inhibitors, both of which act by suppressing increases in postprandial glucose levels 20,21 . Nevertheless, there are no definitive guidelines in regard to PG AUC criteria for glucose intolerance screening or diagnosis.…”

Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects

“…Furthermore, the increase in urinary glucose excretion leads to a negative energy balance and osmotic diuresis, making it a unique antidiabetic agent that reduces also body weight and blood pressure in diabetic patients (Abdul-Ghani and DeFronzo, 2008;Nair and Wilding, 2010). Several SGLT2-selective inhibitors are in various stages of clinical trials (Hussey et al, 2010;Sha et al, 2011;Grempler et al, 2012;Shah et al, 2012), and proof-of-concept has been reported with dapagliflozin (Forxiga; Bristol-Myers Squibb, NY), in phase III studies in patients with T2DM (Bailey et al, 2010;Ghosh et al, 2012).…”