GALVINE

Vildagliptin (LAF237) is an Oral active antihyperglycemic agent that selectively inhibits the dipeptidyl peptidase-4 (DPP-4) enzyme.

It is used to manage type

II diabetes mellitus, where GLP-1 secretion and insulinotropic effects are impaired.

By inhibiting

DPP-4, vildagliptin prevents the degradation of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are incretin hormones that promote insulin secretion and regulate blood glucose levels.

Elevated levels of

GLP-1 and GIP consequently results in improved glycemic control.

In clinical trials, vildagliptin has a relatively low risk of hypoglycemia.

Oral vildagliptin was approved by the European Medicines Agency in for the treatment of type II diabetes mellitus in adults as monotherapy or in combination with metformin, a sulfonylurea, or a thiazolidinedione in patients with inadequate glycemic control following monotherapy.

It is marketed as

Vildagliptin is also available as

Eucreas, a fixed-dose formulation with metformin for adults in who do not adequately glycemic control from monotherapy.

Vildagliptin is currently under investigation in the US.

Vildagliptin is indicated in the treatment of type II diabetes mellitus in adults.

As monotherapy, vildagliptin is indicated in adults inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.

It is also indicated as dual therapy in combination with metformin, a sulphonylurea, or a thiazolidinedione in adults patients with insufficient glycemic control despite maximal tolerated dose of monotherapy.

Vildagliptin is also marketed in a with metformin for the treatment of adults with type II diabetes mellitus who inadequately respond to either monotherapy of vildagliptin or metformin.

This fixed-dose formulation can be used in combination with a sulphonylurea or insulin (i.e., triple therapy) as an adjunct to diet and exercise in adults who do not achieve adequate glycemic control with monotherapy or dual therapy.

Vildagliptin works to improve glycemic control in type II diabetes mellitus by enhancing the glucose sensitivity of beta-cells (β-cells) in pancreatic islets and promoting glucose-dependent insulin secretion.

GLP-1 levels leads to enhanced sensitivity of alpha cells to glucose, promoting glucagon secretion.

Vildagliptin causes an increase in the insulin to glucagon ratio by increasing incretin hormone levels: this results in a decrease in fasting and postprandial hepatic glucose production.

Vildagliptin does not affect gastric emptying.

It also has no effects on insulin secretion or blood glucose levels in individuals with normal glycemic control.

In clinical trials, treatment with vildagliptin 50-100 mg daily in patients with type 2 diabetes significantly improved markers of beta-cells, proinsulin to insulin ratio, and measures of beta-cell responsiveness from the frequently-sampled meal tolerance test.

Vildagliptin has improves glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) levels.

In a fasting state, vildagliptin is rapidly absorbed following oral administration.

Peak plasma concentrations are observed at 1.7 hours following administration.

Plasma concentrations of vildagliptin increase in an approximately dose-proportional manner.

Food delays

T max to 2.5 hours and decreases C max by 19%, but has no effects on the overall exposure to the drug (AUC).

The mean volume of distribution of vildagliptin at steady-state after intravenous administration is 71 L, suggesting extravascular distribution.

About 69% of Oral administered vildagpliptin is eliminated via metabolism not mediated by cytochrome P450 enzymes.

Based on the findings of a rat study, DPP-4 contributes partially to the hydrolysis of vildagliptin.

Vildagliptin is metabolized to pharmacologically inactive cyano (57%) and amide (4%) hydrolysis products in the kidney.

LAY 151 (M20.7) is a major inactive metabolite and a carboxylic acid that is formed via hydrolysis of the cyano moiety: it accounts for 57% of the dose.

Other circulating metabolites reported are an

N-glucuronide (M20.2), an N-amide hydrolysis product (M15.3), two oxidation products, M21.6 and M20.9.

Hover over products below to view reaction partners Vildagliptin Vildagliptin M20.7 metabolite Vildagliptin M15.3 metabolite Vildagliptin M20.2 metabolite Vildagliptin M20.9 metabolite Vildagliptin M21.6 metabolite.

Vildagliptin is eliminated via metabolism.

Following oral administration, approximately 85% of the radiolabelled vildagliptin dose was excreted in urine and about 15% of the dose was recovered in feces.

Of the recovered dose in urine, about 23% accounted for the unchanged parent compound.

The mean elimination half-life following intravenous administration is approximately two hours.

The elimination half-life after oral administration is approximately three hours.

After intravenous administration to healthy subjects, the total plasma and renal clearance of vildagliptin were and 13 L/h, respectively.

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The oral

Lowest published toxic dose (TDLO) is 0.3 mg/kg in rats and 1 mg/kg in mice.

There is limited information regarding overdose with vildagliptin.

In one study, patients experienced muscle pain, mild and transient paresthesia, fever, edema, and a transient increase in lipase levels at a dose of 400 mg. At 600 mg, one subject experienced edema of the feet and hands and increases in creatine phosphokinase (CPK), aspartate aminotransferase (AST), C-reactive protein (CRP) and myoglobin levels.

Supportive management is recommended in case of an overdose.

There is no known antidote, and vildagliptin and its major metabolite cannot be removed via hemodialysis.