EFFECT OF MODERATE HEPATIC INSUFFICIENCY ON THE PHARMACOKINETICS OF SITAGLIPTIN

Main Article Content

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

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

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