EFFECT OF MODERATE HEPATIC INSUFFICIENCY ON THE PHARMACOKINETICS OF SITAGLIPTIN

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 (similar to 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/m(2) +/- 5%). After administration of each dose, blood and urine samples were collected to assess sitagliptin pharmacokinetics. Results The mean AUC(0-infinity) and C-max 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 T-max, apparent terminal t(1/2), fraction of the oral dose excreted into urine (f(e,0-infinity)) and renal clearance (Cl-R) (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.