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QTERNMET XR(dapagliflozin, saxagliptin, and metforminhydrochloride)extended-release tablets(二十三)
ptin to healthy subjects, the mean plasma AUC values for saxagliptin and itsactive metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma Cmax valueswere 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for bothsaxagliptin and its active metabolite was less than 25%.
No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeatedonce daily dosing at any dose level. No dose- and time-dependence were observed in the clearance ofsaxagliptin and its active metabolite over 14 days of once daily dosing with saxagliptin at doses rangingfrom 2.5 to 400 mg.
Absorption
Dapagliflozin
Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usuallyattained within 2 hours under fasting state. The Cmax and AUC values increase dose proportionally withincrease in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability ofdapagliflozin following the administration of a 10 mg dose is 78%. Administration of QTERNMET XR with a standard meal decreases dapagliflozin Cmax by up to 39% and prolongs Tmax by up to 2 hours, butfood does not alter AUC as compared with the fasted state.
Saxagliptin
The median time to maximum concentration (Tmax) following the 5 mg once daily dose was up to 2 hoursfor saxagliptin and 4 hours for its active metabolite. Administration of QTERNMET XR with a standardmeal resulted in an increase in Tmax of saxagliptin by up to 1.5 h and an up to 16% decrease in saxagliptinCmax as compared to fasted conditions. There was an up to 10% increase in the AUC of saxagliptin whengiven with a meal as compared to fasted conditions.
Metformin HCl
Administration of QTERNMET XR with a standard meal resulted in an increase in Tmax of metformin by2 h and no effect on metformin Cmax as compared to fasted conditions. There was an up to 15% increasein the AUC of saxagliptin when given with a meal as compared to fasted conditions. Both high and lowfatmeals had the same effect on the pharmacokinetics of metformin extended-release.
Peak plasma levels of metformin extended-release tablets are approximately 20% lower compared to thesame dose of metformin immediate-release tablets, however, the extent of absorption (as measured byAUC) is similar between extended-release tablets and immediate-release tablets.
At steady state, the AUC and Cmax are less than dose proportional for metformin extended-release withinthe range of 500 to 2000 mg. After repeated administration of metformin extended-release, metformin didnot accumulate in plasma.
Distribution
Dapagliflozin
Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal orhepatic impairment.
Saxagliptin
The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible.
Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) arenot expected to alter the disposition of saxagliptin.
Metformin HCl
Distribution studies with extended-release metformin have not been conducted; however, the apparentvolume of distribution (V/F) of metformin following single oral doses of immediate-release metformin850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitionsinto erythrocytes, most likely as a function of time.
Dapagliflozin
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