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.
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References
Ahren B (1998) Glucagon-like peptide-1 (GLP-1): a gut hormone of potential interest in the treatment of diabetes. Bioessays 20:642–651
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
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
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
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
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
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
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
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
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
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
Lebovitz HE (2002) Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev 18[Suppl 2]:S23–29
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
McLean AJ, Morgan DJ (1991) Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 21:42–69
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
Morgan DJ, McLean AJ (1995) Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update. Clin Pharmacokinet 29:370–391
Nauck M, Stockmann F, Ebert R, Creutzfeldt W (1986) Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29:46–52
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
Rodighiero V (1999) Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet 37:399–431
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
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
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
Wagstaff AJ,Goa KL (2002) Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs 62:1805–1837
Williams RL, Mamelok RD (1980) Hepatic disease and drug pharmacokinetics. Clin Pharmacokinet 5:528–547
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.
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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
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DOI: https://doi.org/10.1007/s00228-007-0312-6