Viglaz Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Vildagliptin is a potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor of the islet enhancer class.
Such inhibition results in increased postprandial and fasting endogenous levels of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) hormone levels.
Vildagliptin is a rapid and complete inhibitor of DPP-4 and is used in the treatment of type 2 diabetes for a 24-hour period.
Vildagliptin improves glucose-dependent insulin secretion by raising the endogenous levels of these incretin hormones and improving beta cell sensitivity to glucose.
Patients with type 2 diabetes who received treatment with 50 to 100 mg per day had seen a significant enhancement in the markers of beta cell function. Vildagliptin does not increase insulin secretion or decrease blood glucose levels in non-diabetic persons, so the degree of beta cell function improvement depends on the initial level of dysfunction.
Vildagliptin raises endogenous GLP-1 levels, which improves the sensitivity of alpha cells to glucose and increases the amount of glucose-appropriate glucagon secretion. Increased levels of incretin hormones cause the insulin/glucagon ratio to rise more rapidly during hyperglycaemia, which lowers blood glucose levels by reducing the production of fasting and postprandial hepatic glucose.
Vildagliptin treatment does not produce the expected delay in gastric emptying caused by elevated GLP-1 levels.
Pharmacokinetics: Absorption: Following oral administration in the fasting state, Vildagliptin is rapidly absorbed with peak plasma concentration observed at 1.75 hours. The absolute bioavailability is 85%. Co-administration with food slightly decreases the rate of absorption of Vildagliptin, as characterized by a 19% decrease in peak concentrations, and a delay in the time to peak plasma concentration to 2.5 hours. There is no change in the extent of absorption, and food does not alter the overall exposure (AUC).
Distribution: The plasma protein binding of Vildagliptin is low (9.3%), and Vildagliptin is distributed equally between plasma and red blood cells. The mean volume of distribution of Vildagliptin at steady-state after intravenous administration (V_ss) is 71 litres, suggesting extravascular distribution.
Metabolism: Approximately 69% of a dose is metabolized, mainly by hydrolysis in the kidney. The major metabolite (LAY151) is pharmacologically inactive and is the hydrolysis product of cyano moiety, accounting for 57% of the dose, followed by the amide hydrolysis product (4% of the dose). DPP-4 contribute partially to the hydrolysis of Vildagliptin as shown in an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolized by CYP450 enzymes to any quantifiable extent. In vitro studies demonstrated that Vildagliptin does not inhibit or induce cytochrome P450 enzymes.
Excretion: Approximately 85% of the dose is excreted into the urine and 15% of the dose is recovered in the feces. Renal excretion of unchanged Vildagliptin accounts for 23% of the dose after oral administration. After intravenous administration to healthy subjects, the total plasma and renal clearances of Vildagliptin are 41 liter/hour and 13 liter/hour, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours and is independent of the dose.
Linearity/non-linearity: Vildagliptin is rapidly absorbed with an absolute oral bioavailability of 85%. Peak plasma concentrations for Vildagliptin and the area under the plasma concentration versus time curve (AUC) increased in an approximately dose-proportional manner over the therapeutic dose range.
Special populations: Gender: No differences in the pharmacokinetics of Vildagliptin were observed between male and female subjects with a diverse range of age and body mass index (BMI). DPP-4 inhibition by Vildagliptin was unaffected by gender.
Obesity: Body Mass Index (BMI) does not show any impact on the pharmacokinetic parameters of Vildagliptin. DPP-4 inhibition by Vildagliptin was unaffected by BMI.
Hepatic impairment: The exposure to Vildagliptin (100 mg) after a single dose in subjects with mild and moderate hepatic impairment (Child-Pugh score 5 to 6 and 7 to 9, respectively) was decreased (20% and 8%, respectively), while exposure to Vildagliptin subjects with severe impairment (Child-Pugh score 10 to 12) was increased by 22%. The maximum change (increase or decrease) in the exposure to Vildagliptin is about 30%, which is not considered to be clinically relevant. There was no correlation between the severity of hepatic function impairment and changes in exposure to Vildagliptin.
The use of Vildagliptin is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >2.5 x ULN.
Renal impairment: The AUC of Vildagliptin increased 1.4, 1.7, and 2-fold in patients with mild (CrCl 50 to less than 80 mL/min), moderate (CrCl 30 to less than 50 mL/min) and severe renal impairment (CrCl less than 30 mL/min), respectively, compared to normal healthy subjects. The AUC of the metabolites LAY151 increased 1.6, 3.2 and 7.3-fold and that of BQS867 increased 1.4, 2.7, and 7.3-fold in patients with mild, moderate and severe renal impairment, respectively, compared to healthy volunteers. Limited data from patients with end stage renal disease (ESRD) indicate that Vildagliptin exposure is similar to that in patients with severe renal impairment. LAY151 concentrations in ESRD patients were approximately 2 to 3-fold higher than in patients with severe renal impairment. Dosage adjustment may be required in patients with renal impairment. Vildagliptin was removed by hemodialysis to a limited data (3% over a 3 to 4-hour hemodialysis session starting 4 hours post dose).
Geriatric patients (65 years or above): In otherwise healthy elderly subjects (≥70 years), the overall exposure to Vildagliptin (100 mg daily) was increased by 32%, with an 18% increase in peak plasma concentration compared to young healthy subjects (18-40 years). These changes are not considered to be clinically relevant. DPP-4 inhibition by Vildagliptin is not affected by age in the age groups studied.
Pediatric patients (below 18 years): No pharmacokinetic data available.
Ethnicity: There was no evidence that ethnicity affects the pharmacokinetics of Vildagliptin.