Pharmacokinetics and pharmacodynamics of vildagliptin in patients with type 2 diabetes mellitus.

Abstract

BACKGROUND:

Vildagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor currently under development for the treatment of type 2 diabetes mellitus.

OBJECTIVES:

To assess the pharmacokinetic and pharmacodynamic characteristics and tolerability of vildagliptin at doses of 10 mg, 25 mg and 100 mg twice daily following oral administration in patients with type 2 diabetes.

METHODS:

Thirteen patients with type 2 diabetes were enrolled in this randomised, double-blind, double-dummy, placebo-controlled, four-period, crossover study. Patients received vildagliptin 10 mg, 25 mg and 100 mg as well as placebo twice daily for 28 days.

RESULTS:

Vildagliptin was absorbed rapidly (median time to reach maximum concentration 1 hour) and had a mean terminal elimination half-life ranging from 1.32 to 2.43 hours. The peak concentration and total exposure increased in an approximately dose-proportional manner. Vildagliptin inhibited DPP-4 (>90%) at all doses and demonstrated a dose-dependent effect on the duration of inhibition. The areas under the plasma concentration-time curves of glucagon-like peptide-1 (GLP-1) [p < 0.001] and glucose-dependent insulinotropic peptide (GIP) [p < 0.001] were increased whereas postprandial glucagon was significantly reduced at the 25 mg (p = 0.006) and 100mg (p = 0.005) doses compared with placebo. As compared with placebo treatment, mean plasma glucose concentrations were decreased by 1.4 mmol/L with the vildagliptin 25 mg dosing regimen and by 2.5 mmol/L with the 100 mg dosing regimen, corresponding to a 10% and 19% reduction, respectively. Vildagliptin was generally well tolerated.

CONCLUSION:

Vildagliptin is likely to be a useful therapy for patients with type 2 diabetes based on the inhibition of DPP-4 and the subsequent increase in incretin hormones, GLP-1 and GIP, and the decrease in glucose and glucagon levels.

• Authors: Yan-Ling He, Denise Serra, Yibin Wang, Joelle Campestrini, Gilles-Jacques Riviere, Carolyn F Deacon, Jens J Holst, Sherwyn Schwartz, Jace C Nielsen, Monica Ligueros-Saylan
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 46 Issue 7 Pg. 577-88 ( 2007) ISSN: 0312-5963 [Print] Switzerland
• PMID: 17596103 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Nitriles
• Pyrrolidines
• Gastric Inhibitory Polypeptide
• Glucagon-Like Peptide 1
• Vildagliptin
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacokinetics, therapeutic use)
• Administration, Oral
• Adult
• Aged
• Area Under Curve
• Blood Glucose (metabolism)
• Cross-Over Studies
• Diabetes Mellitus, Type 2 (blood, drug therapy)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Female
• Gastric Inhibitory Polypeptide (blood)
• Glucagon-Like Peptide 1 (blood)
• Half-Life
• Humans
• Hypoglycemic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Male
• Middle Aged
• Nausea (chemically induced)
• Nitriles (pharmacokinetics, therapeutic use)
• Pyrrolidines (pharmacokinetics, therapeutic use)
• Treatment Outcome
• Vildagliptin
• Vomiting (chemically induced)