Xigduo® [Dapagliflozin, Metformin]

Pharmacological properties

Xigduo Prolong combines two hypoglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type II diabetes mellitus: dapagliflozin, a selective and reversible inhibitor of the sodium-dependent type II glucose cotransporter (nzktg-2), and metformin hydrochloride, biguanide.

Dapagliflozin. Type II sodium glucose cotransporter (SGLT2), which is expressed in the proximal renal tubules, is responsible for the reabsorption of most of the filtered glucose from the tubule lumen. Dapagliflozin is a selective and reversible inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces the reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.

Metformin hydrochloride. Metformin improves glucose tolerance in patients with type II diabetes by lowering basal and postprandial plasma glucose levels. Metformin reduces the synthesis of glucose in the liver, the absorption of glucose in the intestines and increases insulin sensitivity by enhancing peripheral uptake and utilization of glucose. Metformin does not cause hypoglycemia in patients with type II diabetes mellitus or in healthy volunteers, with the exception of unusual circumstances, and does not cause hyperinsulinemia. During treatment with metformin, insulin secretion does not change, while fasting insulin levels and the daily plasma insulin level may actually decrease.

Pharmacodynamics

Dapagliflozin. In healthy study participants and patients with type II diabetes mellitus, after the use of dapagliflozin, an increase in the amount of glucose excreted in urine was observed. About 70 g of glucose was excreted in the urine per day with dapagliflozin at a dose of 5 or 10 mg / day in patients with type II diabetes mellitus for 12 weeks. A similar maximum glucose excretion was noted in the case of dapagliflozin in a daily dose of 20 mg. Such urinary glucose excretion with dapagliflozin also leads to an increase in urine volume.

Cardioelectrophysiology. The use of dapagliflozin was not associated with a clinically significant prolongation of the Q – Tc interval when using the drug in daily doses up to 150 mg (a dose that was 15 times the recommended dose) in a study involving healthy volunteers. In addition, a clinically significant effect on the Q – Tc interval was not detected after the use of healthy volunteers with dapagliflozin in single doses up to 500 mg (dose 50 times the recommended dose).

Pharmacokinetics The use of Xigduo Prolong is considered bioequivalent to the combined use of appropriate doses of dapagliflozin (Forksig) and the original prolonged-release metformin hydrochloride, which are used together in the form of separate tablets.

The use of Xigduo Prolong in healthy volunteers after a standard meal and on an empty stomach provides the same exposure for dapagliflozin and slow release metformin. Compared with fasting, when using the drug during a standard meal, there is a 35% decrease and a delay of 1-2 hours before reaching C_max dapagliflozin in blood plasma. This effect of food intake is not considered clinically significant. Eating does not significantly affect the pharmacokinetics of metformin if used as part of Xigduo Prolong.

Suction

Dapagliflozin. Following oral administration of dapagliflozin C_max in blood plasma, as a rule, is achieved within 2 hours after applying the drug on an empty stomach. C values_max and AUC increase in proportion to an increase in the dose of dapagliflozin in the therapeutic dose range. The absolute bioavailability of dapagliflozin after oral administration of the drug at a dose of 10 mg is 78%. High-Fat Food Lowers C_max dapagliflozin by 50% and increases Tmax by about 1 hour, but does not change the AUC compared with fasting. These changes are not considered clinically significant and dapagliflozin can be applied regardless of food intake.

Metformin hydrochloride. After a single dose of sustained release metformin, the median of reaching C_max equal to 7 hours and has a range of 4–8 hours. The degree of absorption of metformin (as defined by AUC) from slow release metformin tablets increases by about 50% when taken with food.

The effects of food on C_max and Tmax metformin was not observed.

Distribution

Dapagliflozin. Dapagliflozin binds to proteins by approximately 91%. In patients with impaired renal or liver function, the binding of the drug to proteins does not change.

Metformin hydrochloride. Studies of the distribution of metformin sustained release have not been conducted; however, the apparent distribution volume (V / F) of metformin after a single oral administration of metformin with immediate release at a dose of 850 mg averaged 654 ± 358 L. Metformin slightly binds to plasma proteins, in contrast to sulfonylurea, the degree of binding to proteins of which is more than 90%. Metformin penetrates red blood cells.

Metabolism

Dapagliflozin. Dapagliflozin metabolism is mainly mediated by UGT1A9; CYP-mediated metabolism in humans is negligible. Dapagliflozin is extensively metabolized primarily with the formation of dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide is 61% of the dose [¹⁴C] -dapagliflozin 50 mg and is the predominant component in the blood plasma of a person associated with the drug.

Metformin hydrochloride. Studies with iv single-dose administration to healthy volunteers showed that metformin is excreted unchanged in the urine and is not metabolized in the liver (no metabolites were detected in humans) or excretion with bile.

Studies of the metabolism of metformin with a slow release in the case of the use of the drug in tablets have not been conducted.

Breeding

Dapagliflozin. Dapagliflozin and its associated metabolites are mainly excreted by urinary excretion. After application [¹⁴C] -dapagliflozin in a single dose of 50 mg of 75 and 21% of the total radioactivity is excreted in urine and feces, respectively. With urine, less than 2% of the dose is excreted unchanged. With feces in unchanged form, about 15% of the dose of the drug is excreted.

Medium End T_½ from blood plasma, dapagliflozin is about 12.9 hours after a single dose of dapagliflozin at a dose of 10 mg.

Metformin hydrochloride. Renal clearance of metformin exceeds creatinine clearance by approximately 3.5 times, indicating tubular secretion as the main pathway for eliminating metformin. After oral administration of metformin, about 90% of the absorbed drug is excreted by the kidneys during the first 24 hours. T_½ from plasma is about 6.2 hours. T_½ is about 17.6 hours, which indicates the possible participation of red blood cells in the role of depot distribution of the drug.

Individual patient groups

Impaired renal function

Dapagliflozin. At an equilibrium concentration of the drug (20 mg of dapagliflozin 1 time per day for 7 days), patients with type II diabetes mellitus and impaired renal function of mild, moderate or severe degree (as determined by the calculated glomerular filtration rate (rSCF)) had geometric mean values ​​of systemic exposure of dapagliflozin, which were 45% higher, were 2.04 and 3.03 times, respectively, than the same parameters in patients with type II diabetes mellitus with normal renal function. A higher systemic exposure of dapagliflozin in patients with type II diabetes mellitus and with impaired renal function did not lead, respectively, to a higher daily glucose excretion.The daily urinary glucose excretion at an equilibrium concentration of the drug in patients with type II diabetes mellitus and impaired renal function was mild, moderate or severe, respectively, by 42; 80 and 90% lower than in patients with type II diabetes with normal renal function. The effect of hemodialysis on dapagliflozin exposure is unknown.

Metformin hydrochloride. In patients with impaired renal function (by rSCF) T_½ metformin from blood plasma and blood lengthens, and renal clearance decreases in proportion to a decrease in eGFR.

Impaired liver function

Dapagliflozin. In patients with impaired liver function of mild or moderate degree (class A and B according to the Child-Pugh classification), average C_max and AUC of dapagliflozin were respectively 12 and 36% higher compared with the parameters of healthy study participants selected for certain parameters in the control group after a single dose of dapagliflozin at a dose of 10 mg. These differences were not considered clinically significant. In patients with severe liver dysfunction (class C according to the Child-Pugh classification), average C_max and AUC of dapagliflozin were respectively 40 and 67% higher compared with the parameters of healthy study participants selected in certain parameters in the control group.

Metformin hydrochloride. Pharmacokinetic studies of metformin in patients with impaired liver function have not been conducted.

Elderly patients

Dapagliflozin. According to population pharmacokinetic analysis, age does not have a clinically significant effect on systemic exposure of dapagliflosin; therefore, dose adjustment is not required.

Metformin hydrochloride. Some data obtained in the course of controlled pharmacokinetic studies of metformin with the participation of healthy elderly people indicate that the total clearance of metformin is reduced, T_½ lengthens and C_max increases compared with similar indicators in healthy individuals of a young age.

Thus, a change in the pharmacokinetics of metformin with age is primarily due to a change in kidney function.

Pediatric population. The pharmacokinetics of Xigduo Prolong in the pediatric population has not been studied.

Floor

Dapagliflozin. According to population pharmacokinetic analysis, gender does not have a clinically significant effect on systemic exposure of dapagliflosin; therefore, dose adjustment is not required.

Metformin hydrochloride. The pharmacokinetic parameters of metformin in healthy individuals and patients with type II diabetes mellitus did not differ significantly when analyzing data by sex (men - 19, women - 16). In addition, in controlled clinical trials in patients with type II diabetes mellitus, the hypoglycemic effect of metformin was comparable in men and women.

Race

Dapagliflozin. According to population pharmacokinetic analysis, racial affiliation (representatives of the Caucasian, Negroid or Mongoloid race) does not have a clinically significant effect on the systemic exposure of dapagliflozin; therefore, dose adjustment is not required.

Metformin hydrochloride. Studies of the pharmacokinetic parameters of metformin, depending on race, have not been conducted. During controlled clinical trials of the use of metformin in patients with type II diabetes mellitus, the hypoglycemic effect was comparable in representatives of the Caucasian (n = 249), Negroid (n = 51) race and Hispanics (n = 24).

Body mass

Dapagliflozin. According to population pharmacokinetic analysis, body weight does not have a clinically significant effect on systemic exposure of dapagliflosin; therefore, dose adjustment is not required.

Drug interactions.Separate pharmacokinetic studies of drug interaction with Xigduo Prolong have not been conducted, although such studies have been conducted with the individual components of the drug dapagliflozin and metformin.

Assessment of drug interactions in vitro

Dapagliflozin. During in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide did not inhibit the activity of CYP 1A2, 2C9, 2C19, 2D6, 3A4, and did not induce the activity of CYP 1A2, 2B6 or 3A4. Dapagliflozin is a weak substrate for the active carrier of P-glycoprotein (P-gp), and dapagliflozin 3-O-glucuronide is a substrate for the active carrier of OAT3. Dapagliflozin or dapagliflozin 3-O-glucuronide did not significantly inhibit the activity of the active transporters P-gp, OCT2, OAT1 or OAT3. In general, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently used drugs that are substrates for P-gp, OCT2, OAT1 or OAT3.

The effect of other drugs on metformin. In the table. 1 shows the effects of other concurrently used drugs on metformin.

Table 1. The effect of concurrently used drugs on the plasma systemic exposure of metformin

Simultaneously used drug (dosage regimen, mg) *	Metformin (dosage regimen) *, mg	Metformin
		Change indicators† Auc‡,%	Change indicators† Cmax,%
Dose adjustment was not required for the following drugs:
Gliburide (5)	850	↓9§	↓7§
Furosemide (40)	850	↑15§	↑22§
Nifedipine (10)	850	↑9	↑20
Propranolol (40)	850	↓10	↓6
Ibuprofen (400)	850	↑5§	↑7§
Drugs that are secreted by the kidneys by tubular secretion can enhance the accumulation of metformin
Cimetidine (400)	850	↑40	↑60

* Metformin and all the drugs used simultaneously were used as single doses.

^†Percentage change (with / without simultaneous use and without change = 0%); ↑ and ↓ indicate, respectively, an increase and decrease in exposure.

^‡AUC = AUC (INF) (the area of ​​the zone under the curve of concentration versus time from zero to infinity).

^§The ratio