QTERNMET XR(dapagliflozin, saxagliptin, and metforminhydrochloride)extended-release tablets(二十二)
inhibitor that slows the inactivation of the incretin hormones, therebyincreasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrationsin a glucose-dependent manner in patients with type 2 diabetes mellitus.
Metformin HCl
Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal andpostprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinalabsorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake andutilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels andday-long plasma insulin response may actually decrease.
12.2 Pharmacodynamics
Dapagliflozin
Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patientswith type 2 diabetes mellitus following the administration of dapagliflozin. Dapagliflozin dose of 5 or10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion ofapproximately 70 grams of glucose in the urine per day at Week 12. A near maximum glucose excretionwas observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozinalso results in increases in urinary volume [see ADVERSE REACTIONS (6.1)].
Figure 1. Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary
Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with
Type 2 Diabetes Mellitus (T2DM) (Semi-Log Plot)
Saxagliptin
In patients with type 2 diabetes mellitus, administration of saxagliptin inhibits DPP-4 enzyme activity fora 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-foldincrease in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increasedglucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease inglucagon were associated with lower fasting glucose concentrations and reduced glucose excursionfollowing an oral glucose load or a meal.
Cardiac Electrophysiology
Dapagliflozin
Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily dosesup to 150 mg (15 times the recommended maximum dose) in a study of healthy subjects. In addition, noclinically meaningful effect on QTc interval was observed following single doses of up to 500 mg(50 times the recommended maximum daily dose) of dapagliflozin in healthy subjects.
Saxagliptin
In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study usingmoxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningfulprolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the recommendedmaximum daily dose).
12.3 Pharmacokinetics
Dapagliflozin, Saxagliptin and Metformin HClOverall, the pharmacokinetics of dapagliflozin, saxagliptin, and metformin were not affected in aclinically relevant manner when administered as QTERNMET XR.
Saxagliptin
The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin, were similar inhealthy subjects and in patients with type 2 diabetes mellitus. The Cmax and AUC values of saxagliptinand its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mgsingle oral dose of saxagli |
