Influence of hepatic impairment on pharmacokinetics of the human GLP-1 analogue, liraglutide

center dot Liraglutide is a novel human GLP-1 analogue approved for treatment of type 2 diabetes mellitus. Since there is a high prevalence of co-morbid hepatic impairment in this population it is of clinical importance to establish whether the pharmacokinetics of liraglutide are affected by hepatic impairment. WHAT THIS STUDY ADDS center dot This study shows that hepatic impairment does not increase liraglutide exposure. Rather, total exposure tends to decrease with increasing degree of hepatic impairment. AIMS To compare the pharmacokinetics (PK) of a single-dose of liraglutide in subjects with hepatic impairment. METHODS This parallel group, open label trial involved four groups of six subjects with healthy, mild, moderate and severe hepatic impairment, respectively. Each subject received 0.75 mg of liraglutide (s.c., thigh), and blood samples were taken over 72 h for PK assessment. Standard laboratory and safety data were collected. The primary endpoint was area under the plasma liraglutide concentration-time curve from time zero to infinity (AUC(0,infinity)). RESULTS Exposure to liraglutide was not increased by hepatic impairment. On the contrary, mean AUC(0,infinity) was highest for healthy subjects and lowest for subjects with severe hepatic impairment (severe/healthy: 0.56, with 90% CI 0.39, 0.81) and equivalence in this parameter across groups was not demonstrated. C-max also tended to decrease with hepatic impairment (severe/healthy: 0.71, with 90% CI 0.52, 0.97), but t(max) was similar across groups (11.3-13.2 h). There were no serious adverse events, hypoglycaemic episodes or clinically significant changes in laboratory parameters and liraglutide was considered well tolerated. CONCLUSIONS This study indicated no safety concerns regarding use of liraglutide in patients with hepatic impairment. Exposure to liraglutide was not increased by impaired liver function; rather, the results suggest a decreased exposure with increasing degree of hepatic impairment. However, data are not conclusive to suggest a dose increase of liraglutide. Thus, the results indicate that patients with type 2 diabetes mellitus and hepatic impairment can use standard treatment regimens of liraglutide. There is, however, currently limited clinical experience with liraglutide in patients with hepatic impairment.