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0091270007304313v1
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PHARMACOKINETICS

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

Gangadhar Sunkara, PhD, Ron Sabo, Yibin Wang, PhD, Yan-Ling He, PhD, Joelle Campestrini, Mitchell Rosenberg, MD, Dan Howard, PhD and William P. Dole, MD

From Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Sunkara, Mr Sabo, Dr Wang, Ms Campestrini, Dr Howard), Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (Dr He, Dr Dole), and Parkway Research Center Inc, North Miami Beach, Florida (Dr Rosenberg).

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 ß-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)ß]. The 90% confidence intervals of the proportionality coefficient, ß, 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.

Key Words: Type 2 diabetes • vildagliptin • dose proportionality • pharmacokinetics

Address for correspondence: Gangadhar Sunkara, PhD, 435/1187, One Health Plaza, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936.






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