EFFECT OF MODERATE HEPATIC INSUFFICIENCY ON THE PHARMACOKINETICS OF SITAGLIPTIN
Main Article Content
Keywords
Dipeptidyl peptidase-IV, MK-0431, incretins, antihyperglycemic therapy, www.clinicaltrials.gov, NCT00696826
Abstract
Background
Sitagliptin is a highly selective dipeptidyl peptidase-4 inhibitor for the treatment of patients with type 2 diabetes. Sitagliptin is primarily excreted by renal elimination as unchanged drug, with only a small percentage (~16%) undergoing hepatic metabolism.
Objectives
The primary purpose of this study was to evaluate the influence of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin.
Methods
In an open-label study, a single 100 -mg oral dose of sitagliptin was administered to 10 male or female patients with moderate hepatic insufficiency (Child-Pugh’s scores ranged from 7 to 9) and 10 healthy control subjects matched to each patient for race, gender, age (± 5 yrs) and body mass index (BMI kg/m2 ± 5%). After administration of each dose, blood and urine samples were collected to assess sitagliptin pharmacokinetics.
Results
The mean AUC0 -? and Cmax for sitagliptin were numerically, but not significantly (p>0.050), higher in patients with moderate hepatic insufficiency compared with healthy matched control subjects by 21% and 13%, respectively. These slight differences were also not considered to be clinically meaningful. Moderate hepatic insufficiency had no statistically significant effect on the Tmax , apparent terminal t1/2, fraction of the oral dose excreted into urine (fe,0-¥) and renal clearance (ClR) (p>0.100) of sitagliptin. Sitagliptin was generally well tolerated by both patients and subjects; all adverse experiences were transient and rated as mild in intensity.
Conclusions
Moderate hepatic insufficiency has no clinically meaningful effect on the pharmacokinetics of sitagliptin
References
2. Abdelmalek MF, Diehl AM. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med Clin North Am 2007;91:112549.
3. El Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126:460-8.
4. de Marco R, Locatelli F, Zoppini G, Verlato G, Bonora E, Muggeo M. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 1999;22:756-61.
5. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782-7.
6. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002; 287:360-72.
7. Drucker DJ, Nauck MA. GLP-1R agonists (incretin mimetics) and DPP-4 inhibitors (incretin enhancers) for the treatment of type 2 diabetes. Lancet 2006;368:1696-705.
8. Vincent SH, Reed JR, Bergman AJ, et al. Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans. Drug Metab Dispos 2007;35:533-8.
9. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9.
10. Zeng W, Musson DG, Fisher AL, Wang AQ. Determination of MK-0431 in human plasma using high turbulence liquid chromatography online extraction and tandem mass spectrometry. Rapid Commun Mass Spectrom 2006;20:116975.
11. Bergman AJ, Stevens C, Zhou YY, et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: A doubleblind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther 2006;28:5572.
12. Herman GA, Stein PP, Thornberry NA, Wagner JA. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin. Clin Pharmacol Ther 2007;81:761-767.
13. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin 2008;24:489-96.
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