rter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Ertugliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.
Metformin hydrochloride
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings and Precautions (5.7)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
12.2 Pharmacodynamics
Ertugliflozin
Urinary Glucose Excretion and Urinary Volume
Dose-dependent increases in the amount of glucose excreted in urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following single- and multiple-dose administration of ertugliflozin. Dose-response modeling indicates that ertugliflozin 5 mg and 15 mg result in near maximal urinary glucose excretion (UGE). Enhanced UGE is maintained after multiple-dose administration. UGE with ertugliflozin also results in increases in urinary volume.
Cardiac Electrophysiology
The effect of ertugliflozin on QTc interval was eva luated in a Phase 1 randomized, placebo- and positive-controlled 3-period crossover study in 42 healthy subjects. At 6.7 times the therapeutic exposures with maximum recommended dose, ertugliflozin does not prolong QTc to any clinically relevant extent.
12.3 Pharmacokinetics
General Introduction
Ertugliflozin
The pharmacokinetics of ertugliflozin are similar in healthy subjects and patients with type 2 diabetes mellitus. The steady state mean plasma AUC and Cmax were 398 ng∙hr/mL and 81.3 ng/mL, respectively, with 5 mg ertugliflozin once-daily treatment, and 1,193 ng∙hr/mL and 268 ng/mL, respectively, with 15 mg ertugliflozin once-daily treatment. Steady-state is reached after 4 to 6 days of once-daily dosing with ertugliflozin. Ertugliflozin does not exhibit time-dependent pharmacokinetics and accumulates in plasma up to 10-40% following multiple dosing.
Absorption
SEGLUROMET
The effects of a high-fat meal on the pharmacokinetics of ertugliflozin and metformin when administered as SEGLUROMET tablets are comparable to those reported for the individual tablets. Food had no meaningful effect on AUCinf of ertugliflozin and metformin, but reduced mean ertugliflozin Cmax by approximately 41% and metformin Cmax by approximately 29% compared to the fasted condition.
Ertugliflozin
Following single-dose oral administration of 5 mg and 15
