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.
Sunkara
Gangadhar
G
One Health Plaza, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
Sabo
Ron
R
Wang
Yibin
Y
He
Yan-Ling
YL
Campestrini
Joelle
J
Rosenberg
Mitchell
M
Howard
Dan
D
Dole
William P
WP
D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004041:Dietary Fats; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D015233:Models, Statistical; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077597:Vildagliptin
D004041:Dietary Fats; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane