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01-07-2007 | Original Research Article

Pharmacokinetics and Pharmacodynamics of Vildagliptin in Patients with Type 2 Diabetes Mellitus

Authors: Yan-Ling He, PhD, Denise Serra, Yibin Wang, Joelle Campestrini, Gilles-Jacques Riviere, Carolyn F. Deacon, Jens J. Holst, Sherwyn Schwartz, Jace C. Nielsen, Monica Ligueros-Saylan

Published in: Clinical Pharmacokinetics | Issue 7/2007

Abstract

Background

Vildagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor currently under development for the treatment of type 2 diabetes mellitus.

Objectives

To assess the pharmacokinetic and pharmacodynamic characteristics and tolerability of vildagliptin at doses of 10mg, 25mg and l00mg twice daily following oral administration in patients with type 2 diabetes.

Methods

Thirteen patients with type 2 diabetes were enrolled in this randomised, double-blind, double-dummy, placebo-controlled, four-period, crossover study. Patients received vildagliptin 10mg, 25mg and l00mg as well as placebo twice daily for 28 days.

Results

Vildagliptin was absorbed rapidly (median time to reach maximum concentration 1 hour) and had a mean terminal elimination half-life ranging from 1.32 to 2.43 hours. The peak concentration and total exposure increased in an approximately dose-proportional manner. Vildagliptin inhibited DPP-4 (>90%) at all doses and demonstrated a dose-dependent effect on the duration of inhibition. The areas under the plasma concentration-time curves of glucagon-like peptide-1 (GLP-1) [p < 0.001] and glucose-dependent insulinotropic peptide (GIP) [p < 0.001] were increased whereas postprandial glucagon was significantly reduced at the 25mg (p = 0.006) and l00mg (p = 0.005) doses compared with placebo. As compared with placebo treatment, mean plasma glucose concentrations were decreased by 1.4 mmol/L with the vildagliptin 25mg dosing regimen and by 2.5 mmol/L with the lOOmg dosing regimen, corresponding to a 10% and 19% reduction, respectively. Vildagliptin was generally well tolerated.

Conclusion

Vildagliptin is likely to be a useful therapy for patients with type 2 diabetes based on the inhibition of DPP-4 and the subsequent increase in incretin hormones, GLP-1 and GIP, and the decrease in glucose and glucagon levels.

Elliott RM, Morgan LM, Tredger JA, et al. Glucagon-like peptide-1 (7–36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute postprandial and 24-h secretion patterns. J Endocrinol 1993; 138: 159–66PubMedCrossRef

Nauck MA, Bartels E, Orskov C, et al. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-l-(7–36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 1993; 76(4): 912–7PubMedCrossRef

Nauck MA, Bartels E, Orskov C, et al. Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea secondary failure. Diabetes Care 1998; 21(11): 1925–31PubMedCrossRef

Nauck MA, Kleine N, Orskov C, et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993; 36(8): 741–4PubMedCrossRef

Kreymann B, Williams G, Ghatei M, et al. Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet 1987; 2(8571): 1300–4PubMedCrossRef

Naslund E, Bogefors J, Skogar S, et al. GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am J Physiol 1999; 277(3 Pt 2): R910–6PubMed

Delgado-Aros S, Kim DY, Burton DD, et al. Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans. Am J Physiol Gastrointest Liver Physiol 2002; 282(3): G424–31PubMed

Zander M, Madsbad S, Madsen JL, et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002; 359(9309): 824–30PubMedCrossRef

Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev 2002; 18(6): 430–41PubMedCrossRef

10.

Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-l(7–36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 1993; 214(3): 829–35PubMedCrossRef

11.

Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 1995; 80(3): 952–7PubMedCrossRef

12.

Lankas GR, Leiting GR, Roy RS, et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 2005; 54(10): 2988–94PubMedCrossRef

13.

Deacon CF. Therapeutic strategies based on glucagon-like peptide 1. Diabetes 2004; 53(9): 2181–9PubMedCrossRef

14.

Herman GA, Stevens C, Van Dyck K, et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 2005; 78(6): 675–88PubMedCrossRef

15.

He YL, Wang Y, Bullock JM, et al. Pharmacodynamics of vildagliptin in patients with type 2 diabetes during OGTT. J Clin Pharmacol 2007; 47: 633–41PubMedCrossRef

16.

Ahren B, Landin-Olsson M, Jansson PA, et al. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004; 89(5): 2078–84PubMedCrossRef

17.

Pratley RE, Jauffret-Kamel S, Galbreath E, et al. Twelve-week monotherapy with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type 2 diabetes. Horm Metab Res 2006; 38(6): 423–8PubMedCrossRef

18.

Ahren B, Gomis R, Standl E, et al. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004; 27(12): 2874–80PubMedCrossRef

19.

Ristic S, Byiers S, Foley J, et al. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response. Diabetes Obes Metab 2005; 7(6): 692–8PubMedCrossRef

20.

He YL, Barilla D, Ligureos-Saylan M, et al. The pharmacokinetics and DPP-4 inhibition of LAF237 in healthy volunteers. J Clin Pharmacol 2004; 44: 1212

21.

Kim D, Wang L, Beconi M, et al. (2R)-4-oxo-4-[3-(trifluo-romethyl)-5,6-dihydro[l,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl) butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005; 48(1): 141–51PubMedCrossRef

22.

Liljenquist JE, Mueller GL, Cherrington AD, et al. Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man. J Clin Invest 1977; 59(2): 369–74PubMedCrossRef

23.

Dunning BE, Foley JE, Ahren B. Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 2005; 48(9): 1700–13PubMedCrossRef

24.

Muller WA, Faloona GR, Aguilar-Parada E, et al. Abnormal alpha-cell function in diabetes: response to carbohydrate and protein ingestion. N Engl J Med 1970; 283(3): 109–15PubMedCrossRef

25.

Aronoff SL, Bennett PH, Unger RH. Immunoreactive glucagon (IRG) responses to intravenous glucose in prediabetes and diabetes among Pima Indians and normal Caucasians. J Clin Endocrinol Metab 1977; 44(5): 968–72PubMedCrossRef

26.

Ohneda A, Watanabe K, Horigome K, et al. Abnormal response of pancreatic glucagon to glycemie changes in diabetes mellitus. J Clin Endocrinol Metab 1978; 46(3): 504–10PubMedCrossRef

27.

28.

Rosenstock J, Baron MA, Camisasca RP, et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9(2): 175–85PubMedCrossRef

29.

Mari A, Sallas WM, He YL, et al. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes. J Clin Endocrinol Metab 2005; 90(8): 4888–94PubMedCrossRef

30.

Bonadonna RC, Stumvoll M, Fritsche A, et al. Altered homeo-static adaptation of first- and second-phase β-cell secretion in the offspring of patients with type 2 diabetes: studies with a minimal model to assess β-cell function. Diabetes 2003; 52: 470–80PubMedCrossRef

31.

Mari A, Schmitz O, Gastaldelli A, et al. Meal and oral glucose tests for assessment of β-cell function: modeling analysis in normal subjects. Am J Physiol Endocrinol Metab 2002; 283: E1159–66PubMed

Title: Pharmacokinetics and Pharmacodynamics of Vildagliptin in Patients with Type 2 Diabetes Mellitus
Authors: Yan-Ling He, PhD
Denise Serra
Yibin Wang
Joelle Campestrini
Gilles-Jacques Riviere
Carolyn F. Deacon
Jens J. Holst
Sherwyn Schwartz
Jace C. Nielsen
Monica Ligueros-Saylan
Publication date: 01-07-2007
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 7/2007
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200746070-00003

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Pharmacokinetics and Pharmacodynamics of Vildagliptin in Patients with Type 2 Diabetes Mellitus

Abstract

Background

Objectives

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objectives

Methods

Results

Conclusion

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