Skip to main content

Advertisement

Log in

The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes mellitus by increasing α- and β-cell responsiveness to glucose. This study investigated the pharmacokinetics of vildagliptin in patients with hepatic impairment compared with healthy subjects.

Methods

This was an open-label, parallel-group study in patients with mild (n = 6), moderate (n = 6) or severe (n = 4) hepatic impairment and healthy subjects (n = 6). All subjects received a single 100-mg oral dose of vildagliptin, and plasma concentrations of vildagliptin and its main pharmacologically inactive metabolite LAY151 were measured up to 36 h post-dose.

Results

Exposure to vildagliptin (AUC0–∞ and Cmax) decreased non-significantly by 20 and 30%, respectively, in patients with mild hepatic impairment [geometric mean ratio (90% CI): AUC0–∞, 0.80 (0.60, 1.06), p = 0.192; Cmax, 0.70 (0.46, 1.05), p = 0.149]. Exposure to vildagliptin was also decreased non-significantly in patients with moderate hepatic impairment [−8% for AUC0–∞, geometric mean ratio (90% CI): 0.92 (0.69, 1.23), p = 0.630; −23% for Cmax, geometric mean ratio (90% CI): 0.77 (0.51, 1.17), p = 0.293]. In patients with severe hepatic impairment, Cmax was 6% lower than that in healthy subjects [geometric mean ratio (90% CI): 0.94 (0.59, 1.49), p = 0.285], whereas AUC0–∞ was increased by 22% [geometric mean ratio (90% CI): 1.22 (0.89, 1.68), p = 0.816). Across the hepatic impairment groups, LAY151 AUC0–∞ and Cmax were increased by 29–84% and 24–63%, respectively, compared with healthy subjects. The single 100-mg oral dose of vildagliptin was well tolerated by patients with hepatic impairment.

Conclusions

There was no significant difference in exposure to vildagliptin in patients with mild, moderate or severe hepatic impairment; therefore, no dose adjustment of vildagliptin is necessary in patients with hepatic impairment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ahren B (1998) Glucagon-like peptide-1 (GLP-1): a gut hormone of potential interest in the treatment of diabetes. Bioessays 20:642–651

    Article  PubMed  CAS  Google Scholar 

  2. Ahren B, Gomis R, Standl E, Mills D,Schweizer A (2004) Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 27:2874–2880

    Article  PubMed  CAS  Google Scholar 

  3. Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D,Schweizer A (2004) Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 89:2078–2084

    Article  PubMed  CAS  Google Scholar 

  4. Caregaro L, Menon F, Angeli P, Amodio P, Merkel C, Bortoluzzi A, Alberino F, Gatta A (1994) Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis. Arch Intern Med 154:201–205

    Article  PubMed  CAS  Google Scholar 

  5. Deacon CF, Johnsen AH, Holst JJ (1995) 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 80:952–957

    Article  PubMed  CAS  Google Scholar 

  6. Deacon CF, Holst JJ (2006) Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes. Int J Biochem Cell Biol 38:831–844

    Article  PubMed  CAS  Google Scholar 

  7. Food and Drug Administration (2003) Pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. U.S. Department on Health and Human Services. http://www.fda.gov/cber/guidelines.htm. Accessed on March 26, 2007

  8. Hatorp V, Walther KH, Christensen MS, Haug-Pihale G (2000) Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease. J Clin Pharmacol 40:142–152

    Article  PubMed  CAS  Google Scholar 

  9. He Y, Balch A, Campestrini J, Rivere GJ, Seera D, Prasad P (2005) Pharmacokinetics and pharmacodynamics of the DPP-4 inhibitor, LAF237, in patients with type 2 diabetes. Clin Pharmacol Ther 77:56

    Google Scholar 

  10. Holst JJ (2002) Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev 18:430–441

    Article  PubMed  CAS  Google Scholar 

  11. Krarup T, Holst JJ, Larsen KL (1985) Responses and molecular heterogeneity of IR-GIP after intraduodenal glucose and fat. Am J Physiol 249:E195–200

    PubMed  CAS  Google Scholar 

  12. Lebovitz HE (2002) Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev 18[Suppl 2]:S23–29

    Article  PubMed  CAS  Google Scholar 

  13. Mari A, Sallas WM, He YL, Watson C, Ligueros-Saylan M, Dunning BE, Deacon CF, Holst JJ, Foley JE (2005) Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes. J Clin Endocrinol Metab 90:4888–4894

    Article  PubMed  CAS  Google Scholar 

  14. McLean AJ, Morgan DJ (1991) Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 21:42–69

    PubMed  CAS  Google Scholar 

  15. Miyawaki K, Yamada Y, Yano H, Niwa H, Ban N, Ihara Y, Kubota A, Fujimoto S, Kajikawa M, Kuroe A, Tsuda K, Hashimoto H, Yamashita T, Jomori T, Tashiro F, Miyazaki J, Seino Y (1999) Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci USA 96:14843–14847

    Article  PubMed  CAS  Google Scholar 

  16. Morgan DJ, McLean AJ (1995) Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update. Clin Pharmacokinet 29:370–391

    PubMed  CAS  Google Scholar 

  17. Nauck M, Stockmann F, Ebert R, Creutzfeldt W (1986) Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29:46–52

    Article  PubMed  CAS  Google Scholar 

  18. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60:646–649

    Article  PubMed  CAS  Google Scholar 

  19. Rodighiero V (1999) Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet 37:399–431

    Article  PubMed  CAS  Google Scholar 

  20. Sansoe G, Ferrari A, Castellana CN, Bonardi L, Villa E, Manenti F (2002) Cimetidine administration and tubular creatinine secretion in patients with compensated cirrhosis. Clin Sci 102:91–98

    Article  PubMed  CAS  Google Scholar 

  21. Scrocchi LA, Brown TJ, MaClusky N, Brubaker PL, Auerbach AB, Joyner AL, Drucker DJ (1996) Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med 2:1254–1258

    Article  PubMed  CAS  Google Scholar 

  22. Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ (2001) Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50:609–613

    Article  PubMed  CAS  Google Scholar 

  23. Wagstaff AJ,Goa KL (2002) Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs 62:1805–1837

    Article  PubMed  CAS  Google Scholar 

  24. Williams RL, Mamelok RD (1980) Hepatic disease and drug pharmacokinetics. Clin Pharmacokinet 5:528–547

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by Novartis Pharmaceuticals Corporation. This study complied with the current laws of the country where the study was conducted. The study protocol was approved by the relevant local ethical committee review board, and all subjects provided written informed consent. The authors wish to acknowledge the assistance of Dr. Mark Rolfe in collating the contributions of the authors and editing the final manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Y.-L. He.

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, YL., Sabo, R., Campestrini, J. et al. The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin. Eur J Clin Pharmacol 63, 677–686 (2007). https://doi.org/10.1007/s00228-007-0312-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-007-0312-6

Keywords

Navigation