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Dipeptidyl Peptidase 4 (DPP-4) Inhibitor.
Pharmacology: Mechanism of action: Vildagliptin, a member of the islet enhancer class, is a potent and selective dipeptidyl-peptidase-4 (DPP-4) inhibitor that improves glycemic control. Vildagliptin inhibition of DPP-4 results in increased fasting and postprandial endogenous level of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
Pharmacodynamics: The administration of vildagliptin results in rapid and complete inhibition of DPP-4 activity, in patients with type 2 diabetes, administration of vildagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period.
By increasing the endogenous levels of these incretin hormones; vildagliptin enhances the sensitivity of beta cells to glucose resulting in improved glucose-dependent insulin secretion. Treatment with 50 to 100 mg daily in patients with type 2 diabetes significantly improved markers of beta cell function. The degree of improvement in beta-cell function is dependent on the initial degree of impairment; in non-diabetic (normal glycemic) individuals, vildagliptin does not stimulate insulin secretion of reduce glucose levels.
By increasing endogenous GLP-1 levels, vildagliptin enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion. The reduction in inappropriate glucagon during meals in turn attenuates insulin resistance.
The enhanced increase in the insulin/glucagon ratio during hyperglycemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycemia.
The known effect of increased GLP-1 levels to delay gastric emptying is not observed with vildagliptin treatment. In addition, a reduction in postprandial lipemia that is not associated with vildagliptin's incretin mediated effect to improve islet to function has been observed.
Pharmacokinetics: Absorption: Following oral administration in the fasting state, vildagliptin is rapidly absorbed with peak plasma concentrations observed at 1.75 hours. Coadministration 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 (Vss) is 71 liter, suggesting extravascular distribution.
Biotransformation/metabolism: Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose. 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 contributes partially to the hydrolysis of vildagliptin as shown in an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolized by cytochrome P450 enzymes to any quantifiable extent. In vitro studies demonstrated that vildagliptin does not inhibit or induce cytochrome P450 enzymes.
Elimination: Following oral administration of [14C]-vildagliptin, 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 liters/hour and 13 liters/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: BMI does not show any impact on the pharmacokinetic parameters of vildagliptin, DPP-4 inhibition by vildagliptin was unaffected by BMI.
Hepatic Impairment: The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in subjects with mild, moderate, and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison to subjects with normal hepatic function. The exposure to vildagliptin (100 mg) after a single dose in subjects with mild and moderate hepatic impairment was decreased (20% and 8%, respectively), while the exposure for subjects with severe impairment was increased by 22%. The maximum change (increase or decrease) in the exposure to vildagliptin is ~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.
Use is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AT >2.5X the upper limit of normal.
Renal Impairment: The AUC of vildagliptin increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and severe renal impairment, 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 extent (3% over a 3-4 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 once daily) was increased by 32% with an 18% increase in peak plasma concentration compared to younger healthy subjects (18 to 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.
