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 (approximately 16%) undergoing hepatic metabolism.


OBJECTIVE
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.
Migoya
Elizabeth M
EM
Merck Research Laboratories, Rahway, NJ, USA.
Stevens
Catherine H
CH
Bergman
Arthur J
AJ
Luo
Wen-lin
WL
Lasseter
Kenneth C
KC
Dilzer
Stacy C
SC
Davies
Michael J
MJ
Wagner
John A
JA
Herman
Gary A
GA
D000284:Administration, Oral; D000368:Aged; D019540:Area Under Curve; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D048550:Hepatic Insufficiency / Q000503:physiopathology*; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics*
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D000068900:Sitagliptin Phosphate