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

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 (r(2) = 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 (AUC(0-infinity)) and maximum plasma concentration (C(max)). Dose proportionality was assessed using a statistical power model [X = alpha x (dose)(beta)]. The 90% confidence intervals of the proportionality coefficient, beta, for AUC(0-infinity) (1.15-1.19) and C(max) (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 AUC(0-infinity) and C(max) but no dose-dependent changes in time to reach C(max) or terminal elimination half-life. Administration of vildagliptin 100 mg following a high-fat meal decreased C(max) by 19% and AUC(0-infinity) 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.