Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin.

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 (approximately 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 AUC(0-infinity) 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 t(1/2), fraction of the oral dose excreted into urine (f(e,0-infinity)) 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.

• Authors: Elizabeth M Migoya, Catherine H Stevens, Arthur J Bergman, Wen-lin Luo, Kenneth C Lasseter, Stacy C Dilzer, Michael J Davies, John A Wagner, Gary A Herman
• Journal: The Canadian journal of clinical pharmacology = Journal canadien de pharmacologie clinique (Can J Clin Pharmacol) Vol. 16 Issue 1 Pg. e165-70 ( 2009) ISSN: 1710-6222 [Electronic] Canada
• PMID: 19221403 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dipeptidyl-Peptidase IV Inhibitors
• Pyrazines
• Triazoles
• Sitagliptin Phosphate

Topics

• Administration, Oral
• Aged
• Area Under Curve
• Case-Control Studies
• Diabetes Mellitus, Type 2 (complications, drug therapy)
• Dipeptidyl-Peptidase IV Inhibitors (adverse effects, pharmacokinetics)
• Female
• Half-Life
• Hepatic Insufficiency (physiopathology)
• Humans
• Liver Function Tests
• Male
• Middle Aged
• Pyrazines (adverse effects, pharmacokinetics)
• Severity of Illness Index
• Sitagliptin Phosphate
• Triazoles (adverse effects, pharmacokinetics)