J Clin Pharmacol
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First published on July 26, 2007, doi:10.1177/0091270007304313

The Journal of Clinical Pharmacology 2007;47:1152.

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©© 2007 American College of Clinical Pharmacology, Inc.
The Journal of Clinical Pharmacology , 10.1177/0091270007304313

Article

Dose Proportionality and the Effect of Food on Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, in Healthy Volunteers

Gangadhar Sunkara 1*, Ron Sabo 1, Yibin Wang 1, Yan-Ling He 2, Joelle Campestrini 1, Mitchell Rosenberg 3, Dan Howard 1, and William P. Dole 2

1 Novartis Pharmaceuticals Corporation
2 Novartis Institutes for Biomedical Research
3 Parkway Research Center Inc

* To whom correspondence should be addressed. E-mail: gangadhar.sunkara{at}novartis.com.


  Abstract
Vildagliptin is a potent and selective dipeptidyl peptidase IV inhibitor in development for the treatment of type 2 diabetes that improves glycemic control by enhancing {alpha}- and {beta}-cell responsiveness to glucose. Two open-label, single-dose, randomized, crossover studies in healthy subjects (ages 18-45 years) investigated the dose proportionality of vildagliptin pharmacokinetics (n = 20) and the effect of food (n = 24) on vildagliptin pharmacokinetics. There was a linear relationship (r2 = 0.999) between vildagliptin doses of 25, 50, 100, and 200 mg and area under the plasma concentration–time curve from time zero to infinity (AUC0-{infty}) and maximum plasma concentration (Cmax). Dose proportionality was assessed using a statistical power model [X = {alpha}·(dose){beta}]. The 90% confidence intervals of the proportionality coefficient, {beta}, for AUC0-{infty} (1.15-1.19) and Cmax (1.04-1.14) indicated that deviations from dose proportionality were small (<7.7%). Doubling of dose led to 2.1- to 2.3-fold increases in AUC0-{infty} and Cmax but no dose-dependent changes in time to reach Cmax or terminal elimination half-life. Administration of vildagliptin 100 mg following a high-fat meal decreased Cmax by 19% and AUC0-{infty} by 10%. Vildagliptin displays approximately dose-proportional pharmacokinetics over the 25- to 200-mg dose range, and administration with food has no clinically relevant effect on vildagliptin pharmacokinetics.
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