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Pharmacodynamics of Vildagliptin in Patients With Type 2 Diabetes During OGTT

From Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (Dr He); Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Wang, Dr Ligueros-Saylan, Dr Foley); State University at Buffalo College of Pharmacy and Pharmaceutical Sciences, Buffalo, New York (Dr Bullock); Department of Medical Physiology, Panum Institute, University of Copenhagen, Denmark (Dr Deacon, Dr Holst); and PharmaWrite LLC, Princeton, New Jersey (Dr Dunning).

This randomized, open-label, placebo-controlled, 7-period crossover study assessed dose-response relationships following single oral doses (10-400 mg) of vildagliptin in 16 patients with type 2 diabetes mellitus. Plasma levels of parent drug, dipeptidyl peptidase-4 activity, glucose, insulin, and glucagon were measured during 75-g oral glucose tolerance tests performed after an overnight fast, 30 minutes after drug administration. The t_max for parent drug was observed between 0.5 and 1.5 hours postdose. Both C_max and AUC_{0-8 h} increased dose proportionately. Both onset and duration of dipeptidyl peptidase-4 inhibition were dose dependent, but >90% inhibition occurred within 45 minutes and was maintained for 4 hours after each dose. Glucose excursions and glucagon levels during oral glucose tolerance tests were significantly and similarly decreased after each dose of vildagliptin, and insulin levels were significantly and similarly increased after each dose level. Unlike findings during mixed-meal challenges, vildagliptin increases plasma insulin levels during oral glucose tolerance tests in patients with type 2 diabetes mellitus.

Key Words: Dipeptidyl peptidase IV • GLP-1 • GIP • insulin • glucagon • glucose

Address for reprints: Address for correspondence: Yan-Ling He, PhD, DMSc, Exploratory Development, Novartis Institutes of Biomedical Research Inc, 400 Technology Square, Building 605, Rm 811, Cambridge, MA 02139-3584; e-mail: yanling.he{at}novartis.com.

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				K. Azuma, Z. Radikova, J. Mancino, F. G. S. Toledo, E. Thomas, C. Kangani, C. Dalla Man, C. Cobelli, J. J. Holst, C. F. Deacon, et al. Measurements of Islet Function and Glucose Metabolism with the Dipeptidyl Peptidase 4 Inhibitor Vildagliptin in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 459 - 464. [Abstract] [Full Text] [PDF]

				Y.-L. He, M. Ligueros-Saylan, G. Sunkara, R. Sabo, C. Zhao, Y. Wang, J. Campestrini, F. Pommier, K. Dole, A. Marion, et al. Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, Has No Pharmacokinetic Interactions With the Antihypertensive Agents Amlodipine, Valsartan, and Ramipril in Healthy Subjects J. Clin. Pharmacol., January 1, 2008; 48(1): 85 - 95. [Abstract] [Full Text] [PDF]