QTERNMET XR(dapagliflozin, saxagliptin, and metforminhydrochloride)extended-release tablets(二十四)
ism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is aminor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yielddapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accountedfor 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in humanplasma.
Saxagliptin
The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The majormetabolite of saxagliptin is also a DPP-4 inhibitor, which is one-half as potent as saxagliptin. Therefore,strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active
metabolite [see DRUG INTERACTIONS (7)].
Metformin HCl
Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged inthe urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) orbiliary excretion.
Metabolism studies with extended-release metformin tablets have not been conducted.
Elimination
Dapagliflozin
Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces,respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% ofthe dose is excreted as parent drug. The mean plasma terminal half-life (t1/2) for dapagliflozin isapproximately 12.9 hours following a single oral dose of dapagliflozin 10 mg.
Saxagliptin
Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of[14C]-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its activemetabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin(~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min),suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in
feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from thegastrointestinal tract. Following a single oral dose of saxagliptin 5 mg to healthy subjects, the meanplasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubularsecretion is the major route of metformin elimination. Following oral administration, approximately 90%of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination
half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours,suggesting that the erythrocyte mass may be a compartment of distribution.
Specific Populations
Effects of Age, Gender, Race, and Body Weight on PharmacokineticsBased on a population pharmacokinetic analysis, age, gender, race, and body weight do not have a
clinically meaningful effect on the pharmacokinetics of dapagliflozin and saxagliptin.
Renal Impairment
Dapagliflozin: At steady state (20 mg once daily dapagliflozin for 7 days), patients with type 2 diabeteswith mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemicexposures of dapagliflozin tha |
