Galvus meth
Combined oral hypoglycemic drug. The drug Galvus Met contains two hypoglycemic agents with different mechanisms of action: vildagliptin, which belongs to the class of dipeptidyl peptidase-4 inhibitors (DPP-4), and metformin (in the form of hydrochloride), a representative of the biguanide class. The combination of these components allows for more effective control of blood glucose concentrations in patients with type 2 diabetes mellitus within 24 hours.
Vildagliptin
Vildagliptin is a representative of the class of stimulants of the islet apparatus of the pancreas, selectively inhibits the enzyme DPP-4, which destroys glucagon-like peptide type 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
Rapid and complete inhibition of DPP-4 activity causes an increase in both basal and meal-stimulated secretion of GLP-1 and GIP from the intestine into the systemic circulation throughout the day.
By increasing the concentration of GLP-1 and GIP, vildagliptin causes an increase in the sensitivity of pancreatic β-cells to glucose, which leads to an improvement in glucose-dependent insulin secretion. The degree of improvement in β-cell function depends on the degree of initial damage; Thus, in individuals without diabetes mellitus (with normal plasma glucose concentrations), vildagliptin does not stimulate insulin secretion and does not reduce glucose concentrations.
By increasing the concentration of endogenous GLP-1, vildagliptin increases the sensitivity of α-cells to glucose, which leads to improved glucose-dependent regulation of glucagon secretion. The reduction in elevated glucagon concentrations during meals, in turn, causes a decrease in insulin resistance.
An increase in the insulin/glucagon ratio against the background of hyperglycemia, caused by an increase in the concentration of GLP-1 and GIP, causes a decrease in the production of glucose by the liver both during and after meals, which leads to a decrease in the concentration of glucose in the blood plasma.
In addition, with the use of vildagliptin, a decrease in plasma lipid concentrations after meals was observed, but this effect is not associated with its effect on GLP-1 or GIP and improvement of pancreatic islet cell function.
It is known that an increase in the concentration of GLP-1 can lead to a delay in gastric emptying, but no such effect is observed with the use of vildagliptin.
When vildagliptin was administered to 5759 patients with type 2 diabetes mellitus for 52 weeks as monotherapy or in combination with metformin, sulfonylureas, thiazolidinedione, or insulin, there was a significant long-term decrease in the concentration of glycated hemoglobin (HbA1c) and fasting blood glucose.
Metformin
Metformin improves glucose tolerance in patients with type 2 diabetes mellitus by reducing plasma glucose concentrations both before and after meals. Metformin reduces the production of glucose by the liver, reduces the absorption of glucose in the intestine and reduces insulin resistance by enhancing the uptake and utilization of glucose by peripheral tissues. Unlike sulfonylurea derivatives, metformin does not cause hypoglycemia either in patients with type 2 diabetes mellitus or in healthy individuals (except in special cases). Therapy with the drug does not lead to the development of hyperinsulinemia. When using metformin, insulin secretion does not change, while the concentration of insulin in the blood plasma on an empty stomach and during the day may decrease.
Metformin induces intracellular glycogen synthesis by acting on glycogen synthase and enhances glucose transport by certain membrane glucose transport proteins (GLUT-1 and GLUT-4).
When using metformin, there is a beneficial effect on lipoprotein metabolism: a decrease in the concentration of total cholesterol, LDL cholesterol and TG, which is not associated with the effect of the drug on the concentration of glucose in plasma.
Vildagliptin + metformin
When using combination therapy with vildagliptin and metformin in daily doses of 1500-3000 mg metformin and 50 mg vildagliptin 2 times a day for 1 year, a statistically significant persistent decrease in blood glucose concentration was observed (determined by a decrease in HbA1c) and an increase in the proportion of patients with a decrease the HbA1c indicator was at least 0.6-0.7% (compared to the group of patients who continued to receive only metformin).
In patients receiving the combination of vildagliptin and metformin, there was no statistically significant change in body weight compared to baseline. 24 weeks after the start of treatment, in groups of patients receiving vildagliptin in combination with metformin, a decrease in systolic and diastolic blood pressure was observed in patients with arterial hypertension.
When a combination of vildagliptin and metformin was used as initial therapy in patients with type 2 diabetes mellitus for 24 weeks, a dose-dependent decrease in HbA1c and body weight was observed compared with monotherapy with these drugs. The incidence of hypoglycemia was minimal in both treatment groups.
When using vildagliptin (50 mg 2 times / day) with or without metformin in combination with insulin (average dose 41 units), the HbA1c level in patients in a clinical study decreased statistically significantly - by 0.72% (initial value - on average 8.8%). The incidence of hypoglycemia in the treatment group was comparable to the incidence of hypoglycemia in the placebo group.
When vildagliptin (50 mg 2 times/day) was used together with metformin (≥1500 mg) in combination with glimepiride (≥4 mg/day) in patients in a clinical study, the HbA1c indicator statistically significantly decreased by 0.76% (from an average level of 8.8 %).
Pharmacokinetics
Vildagliptin
Suction
When taken orally on an empty stomach, vildagliptin is rapidly absorbed, and its Cmax is reached 1.75 hours after administration. When taken simultaneously with food, the rate of absorption of vildagliptin decreases slightly: there is a decrease in Cmax by 19% and an increase in the time to reach it to 2.5 hours. However, food intake does not affect the degree of absorption and AUC.
Vildagliptin is rapidly absorbed, with absolute bioavailability after oral administration of 85%. Cmax and AUC increase approximately proportionally to dose over the therapeutic dose range.
Distribution
The binding of vildagliptin to plasma proteins is low (9.3%). The drug is distributed evenly between plasma and red blood cells. The distribution of vildagliptin presumably occurs extravascularly, Vss after IV administration is 71 L.
Metabolism
Biotransformation is the main route of elimination of vildagliptin. In the human body, 69% of the drug dose is converted. The main metabolite, LAY151 (57% of the dose), is pharmacologically inactive and is a product of hydrolysis of the cyano component. About 4% of the drug dose undergoes amide hydrolysis.
Experimental studies indicate a positive effect of DPP-4 on the hydrolysis of the drug. Vildagliptin is not metabolized with the participation of cytochrome P450 isoenzymes. According to in vitro studies, vildagliptin is not a substrate and does not inhibit or induce CYP450 isoenzymes.
Removal
After oral administration of the drug, about 85% of the dose is excreted by the kidneys and 15% through the intestines; renal excretion of unchanged vildagliptin is 23%. With intravenous administration, the average T1/2 reaches 2 hours, the total plasma clearance and renal clearance of vildagliptin are 41 l/h and 13 l/h, respectively. T1/2 after oral administration is about 3 hours, regardless of dose.
Pharmacokinetics in special clinical situations
Gender, BMI and ethnicity do not affect the pharmacokinetics of vildagliptin.
In patients with mild to moderate liver dysfunction (6-10 points according to the Child-Pugh classification), after a single dose of the drug, a decrease in the bioavailability of vildagliptin is observed by 8% and 20%, respectively. In patients with severe liver failure (Child-Pugh score 12), the bioavailability of vildagliptin increases by 22%. The maximum change in vildagliptin bioavailability, an increase or decrease of up to an average of 30%, is not clinically significant. There was no correlation between the severity of liver dysfunction and the bioavailability of the drug.
In patients with mild, moderate or severe renal impairment, the AUC of vildagliptin increased compared to healthy volunteers by 1.4, 1.7 and 2 times, respectively. The AUC of the LAY151 metabolite increased by 1.6, 3.2 and 7.3 times, and the AUC of the BQS867 metabolite by 1.4, 2.7 and 7.3 times in patients with mild, moderate and severe renal impairment, respectively. Limited data in patients with end-stage chronic kidney disease (CKD) indicate that rates in this group are similar to those in patients with severe renal impairment. The concentration of the LAY151 metabolite in patients with end-stage CKD increased 2-3 times compared to the concentration in patients with severe renal impairment. The elimination of vildagliptin during hemodialysis is limited (3% during a procedure lasting more than 3-4 hours 4 hours after a single dose of the drug).
The maximum increase in bioavailability of the drug by 32% (increase in Cmax by 18%) in patients over 70 years of age is not clinically significant and does not affect DPP-4 inhibition.
The pharmacokinetic properties of vildagliptin in children and adolescents under 18 years of age have not been established.
Metformin
Suction
The absolute bioavailability of metformin when taken orally at a dose of 500 mg on an empty stomach was 50-60%. Cmax is reached 1.81-2.69 hours after administration. When the dose of the drug was increased from 500 mg to 1500 mg, or when taken orally in doses from 850 mg to 2250 mg, a slower increase in pharmacokinetic parameters was observed (than would be expected for a linear relationship). This effect is due not so much to a change in the excretion of the drug as to a slowdown in its absorption. During food intake, the degree and rate of absorption of metformin also decreased slightly. Thus, with a single dose of 850 mg of the drug with food, there was a decrease in Cmax and AUC by approximately 40% and 25%, and an increase in Tmax by 35 minutes. The clinical significance of these facts has not been established.
Distribution
With a single oral dose of 850 mg, the apparent Vd of metformin is 654 ± 358 l. The drug practically does not bind to plasma proteins, while sulfonylurea derivatives bind to them by more than 90%. Metformin penetrates into red blood cells (this process is likely to increase over time). When using metformin according to a standard regimen (standard dose and frequency of administration), Css of the drug in the blood plasma is achieved within 24-48 hours and, as a rule, does not exceed 1 mcg/ml. During controlled clinical studies, the Cmax of metformin in blood plasma did not exceed 5 mcg/ml (even when taken in high doses).
Metabolism and excretion
With a single intravenous administration to healthy volunteers, metformin is excreted unchanged by the kidneys. At the same time, it is not metabolized in the liver (no metabolites have been identified in humans) and is not excreted in the bile.
Since the renal clearance of metformin is approximately 3.5 times higher than QC, the main route of elimination of the drug is tubular secretion. When taken orally, approximately 90% of the absorbed dose is excreted by the kidneys within the first 24 hours; while T1/2 from blood plasma is about 6.2 hours. T1/2 of metformin from whole blood is about 17.6 hours, which indicates the accumulation of a significant part of the drug in erythrocytes.
Pharmacokinetics in special clinical situations
The gender of patients does not affect the pharmacokinetics of metformin.
The pharmacokinetic properties of metformin have not been studied in patients with liver failure.
In patients with impaired renal function (assessed by CK), T1/2 of metformin from plasma and whole blood increases, and its renal clearance decreases in proportion to the decrease in CK.
According to limited data from pharmacokinetic studies, in healthy people aged ≥ 65 years, a decrease in the total plasma clearance of metformin and an increase in T1/2 and Cmax were observed compared with young individuals. These features of the pharmacokinetics of metformin in individuals over 65 years of age are probably primarily associated with changes in renal function. Therefore, in patients over 80 years of age, the use of Galvus Met is possible only with normal QC.
The pharmacokinetic properties of metformin in children and adolescents under 18 years of age have not been established.
There is no evidence of the influence of patient ethnicity on the pharmacokinetic properties of metformin. In controlled clinical studies of metformin in patients with type 2 diabetes mellitus of different ethnicities, the hypoglycemic effect of the drug was manifested to the same extent.
Vildagliptin + Metformin
Studies have shown bioequivalence in terms of AUC and Cmax of Galvus Met at three different dosages (50 mg/500 mg, 50 mg/850 mg and 50 mg/1000 mg) and vildagliptin and metformin taken in corresponding doses in the form of separate tablets.
Food does not affect the degree and rate of absorption of vildagliptin as part of the drug Galvus Met. The Cmax and AUC values of metformin as part of the drug Galvus Met when taken simultaneously with food decreased by 26% and 7%, respectively. In addition, the absorption of metformin slowed down during food intake, which led to an increase in Tmax (from 2 to 4 hours). A similar change in Cmax and AUC during food intake was also observed when metformin was used alone, but in the latter case the changes were less significant.
The effect of food on the pharmacokinetics of vildagliptin and metformin as part of the drug Galvus Met did not differ from that when taking both drugs separately.
