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Pharmacotherapeutic group: Drugs used in diabetes. Combinations of oral blood glucose-lowering drugs. ATC code: A10BD15.
Pharmacology: Mechanism of action: Dapagliflozin: Most of the reabsorption of filtered glucose from the tubular lumen is carried out by sodium-glucose cotransporter 2 (SGLT2), which is expressed in the proximal renal tubules. SGLT2 is inhibited by dapagliflozin. Dapagliflozin decreases the reabsorption of filtered glucose by blocking SGLT2, which encourages the excretion of glucose through the urine. Additionally, dapagliflozin enhances sodium transport to the distal tubule and decreases salt reabsorption. This may affect a number of physiological processes, such as reducing the heart's pre- and afterload, downregulating sympathetic activity, and lowering intraglomerular pressure, which is thought to be caused by an increase in tubuloglomerular feedback.
Metformin HCl: By reducing both basal and postprandial plasma glucose, the antihyperglycemic medication metformin helps people with type 2 diabetes mellitus improve their glucose tolerance. Metformin enhances insulin sensitivity by boosting peripheral glucose uptake and utilization while reducing intestinal glucose absorption and hepatic glucose synthesis. Insulin secretion is unaffected by metformin therapy, however fasting insulin levels and the daytime plasma insulin response may drop.
Pharmacodynamics: General: Dapagliflozin: After taking dapagliflozin, both healthy individuals and patients with type 2 diabetes mellitus showed increases in the amount of glucose expelled in their urine. Patients with type 2 diabetes mellitus who received dosages of 5 or 10 mg of dapagliflozin daily for 12 weeks excreted about 70 grams of glucose in their urine daily. The daily dosage of 20 mg of dapagliflozin was found to result in a near-maximum excretion of glucose. Urine volume increases as a result of dapagliflozin-induced glucose excretion in the urine. For the 10 mg dosage, the increase in urine glucose excretion typically returns to baseline after 3 days of stopping dapagliflozin.
Cardiac Electrophysiology: In a trial of healthy subjects, dapagliflozin did not cause a clinically significant lengthening of the QTc interval at daily doses up to 150 mg (15 times the recommended maximum dose). Furthermore, in healthy patients, single doses of dapagliflozin up to 500 mg (50 times the recommended maximum dose) did not result in any clinically significant change in QTc interval.
Pharmacokinetics: Both dapagliflozin and metformin extended-release were exposed to the same degree when Dapagliflozin and Metformin HCl (As Extended Release) Tablets was administered to healthy subjects following a typical meal as opposed to when they were fasting. The typical meal caused the peak plasma concentrations of dapagliflozin to decrease by 35% and to be delayed by 1 to 2 hours when compared to the fasted condition. It is not thought that this food impact has any clinical significance. When taking Dapagliflozin and Metformin HCl (As Extended Release) Tablets combo pills, food has no discernible impact on the pharmacokinetics of metformin.
Absorption: Dapagliflozin: When dapagliflozin is taken orally, the maximum plasma concentration (Cmax) is typically reached in two hours while fasting. As the dosage of dapagliflozin increases within the therapeutic dose range, the Cmax and AUC values rise proportionately. After a dose of 10 mg of dapagliflozin is administered, its absolute oral bioavailability is 78%. When dapagliflozin is administered with a high-fat meal, its Cmax can drop by as much as 50% and its Tmax can be prolonged by around an hour. However, the AUC remains unchanged when compared to the fasted condition. It is thought that these alterations are not clinically significant, and dapagliflozin can be taken with or without food.
Metformin HCl: Cmax is reached with a median value of 7 hours and a range of 4 to 8 hours after a single oral dose of metformin HCl extended-release. When the metformin HCl extended-release tablet was taken with food, the amount of metformin absorption (as shown by AUC) increased by almost 50%. Food had no effect on metformin's Cmax or Tmax. Peak plasma levels of metformin HCl extended-release tablets are about 20% lower than those of metformin HCl immediate-release tablets at the same dose, although the degree of absorption (as determined by AUC) is comparable between the two types of tablets.
Distribution: Dapagliflozin: About 91% of dapagliflozin is protein bound. Patients with hepatic or renal impairment do not have changed protein binding.
Metformin HCl: The apparent volume of distribution (V/F) of metformin after single oral dosages of immediate-release metformin 850 mg averaged 654 ± 358 L; however, distribution studies using extended-release metformin have not been carried out. Unlike sulfonylureas, which are more than 90% protein bound, metformin is only weakly linked to plasma proteins. Erythrocytes are where metformin divides.
Metabolism: Dapagliflozin: UGT1A9 is the primary mediator of dapagliflozin metabolism; CYP-mediated metabolism is a minor human clearance mechanism. The main result of dapagliflozin's extensive metabolism is the inactive metabolite dapagliflozin 3-O-glucuronide. Dapagliflozin 3-O-glucuronide is the main drug-related component in human plasma and made up 61% of a 50 mg [14C]-dapagliflozin dose.
Metformin HCl: Metformin does not undergo hepatic metabolism (no metabolites have been found in humans) or biliary excretion, according to intravenous single-dose trials conducted in healthy people.
No research has been done on the metabolism of extended-release metformin pills.
Elimination: Dapagliflozin: The renal route is principally responsible for the elimination of dapagliflozin and its associated metabolites. Urine and feces contain 75% and 21% of the total radioactivity after a single 50 mg dose of [14C]-dapagliflozin, respectively. Less than 2% of the dosage is eliminated as parent medication in the urine. About 15% of the dosage is eliminated as parent medication in the feces. After a single oral dose of dapagliflozin (10 mg), the mean plasma terminal half-life (t1/2) is roughly 12.9 hours.
Metformin HCl: The main method of metformin elimination is tubular secretion, as renal clearance is roughly 3.5 times higher than creatinine clearance. Within the first 24 hours after oral administration, the kidneys remove around 90% of the medication that has been absorbed, with a half-life of about 6.2 hours for plasma clearance. The elimination half-life in blood is roughly 17.6 hours, indicating that the erythrocyte bulk might constitute a distribution compartment.
Specific Populations: Geriatric Patients: Dapagliflozin: Age has no clinically significant impact on dapagliflozin systemic exposures, according to a population pharmacokinetic analysis.
Metformin HCl: Limited information from controlled pharmacokinetic trials of metformin in healthy older adults indicates that, in comparison to healthy young subjects, the total plasma clearance of metformin is reduced, the half-life is extended, and the Cmax is raised. These findings suggest that a change in renal function is the main cause of the aging-related shift in metformin pharmacokinetics.
Pediatric Patients: Dapagliflozin: Dapagliflozin's pharmacokinetics and pharmacodynamics (glucosuria) in children with type 2 diabetes mellitus between the ages of 10 and 17 were comparable to those seen in adults with the same level of renal function.
Metformin HCl: The geometric mean metformin Cmax and AUC difference between pediatric type 2 diabetes children (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function, was less than 5% following the administration of a single oral metformin 500 mg tablet with food.
Male and Female Patients: Dapagliflozin: Gender had no clinically significant impact on systemic exposures to dapagliflozin, according to a population pharmacokinetic investigation.
Metformin HCl: When evaluated by gender, there were no significant differences in metformin pharmacokinetic parameters between patients with type 2 diabetes mellitus and healthy volunteers (males = 19, females = 16). Similarly, metformin's antihyperglycemic efficacy was similar in males and females in controlled clinical trials including patients with type 2 diabetes.
Racial or Ethnic Groups: Dapagliflozin: Race (White, Black or African American, or Asian) has no clinically significant impact on systemic exposures to dapagliflozin, according to a population pharmacokinetic analysis.
Metformin HCl: There have been no research on the pharmacokinetic characteristics of metformin by race. Whites (n=249), Black or African Americans (n=51), and Hispanic or Latino Ethnicity (n=24) all experienced similar antihyperglycemic effects from metformin in controlled clinical trials in patients with type 2 diabetes mellitus.
Patients with Renal Impairment: Dapagliflozin: Adult patients with type 2 diabetes mellitus who had mild, moderate, or severe renal impairment (as assessed by eGFR) at steady-state (20 mg once daily dapagliflozin for 7 days) had geometric mean systemic exposures of dapagliflozin that were, respectively, 45%, 100%, and 200% higher than those who had normal renal function. Patients with type 2 diabetes mellitus who had renal impairment and increased systemic exposure to dapagliflozin did not have a correspondingly higher 24-hour urine glucose excretion. Compared to patients with type 2 diabetes mellitus who had normal renal function, those with mild, moderate, and severe renal impairment had steady-state 24-hour urine glucose excretion that was 42%, 80%, and 90% lower, respectively. It is unknown how hemodialysis affects exposure to dapagliflozin.
Metformin HCl: Metformin's blood and plasma half-lives are longer and renal clearance is lower in patients with impaired renal function.
Patients with Hepatic Impairment: Dapagliflozin: Following a single dose of 10 mg dapagliflozin, the mean Cmax and AUC of dapagliflozin in adult patients with mild and moderate hepatic impairment (Child-Pugh classifications A and B) were up to 12% and 36% higher, respectively, than in healthy matched control subjects. Clinical significance was not attributed to these changes. Compared to healthy matched controls, the mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, in adult patients with severe hepatic impairment (Child-Pugh class C).
Metformin HCl: There are no known pharmacokinetic investigations of metformin in hepatic impairment patients.
