Pharmacokinetics of linagliptin in subjects with hepatic impairment

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Linagliptin is an oral, highly selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor that was approved in the United States, Europe and elsewhere in 2011 for the treatment of type 2 diabetes mellitus. • The elimination of linagliptin is primarily non‐renal. Therefore, a potential effect of hepatic impairment on the elimination of linagliptin may have important implications for dosing recommendations. WHAT THIS STUDY ADDS • This study shows that mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing as compared with normal hepatic function. • No linagliptin dose adjustment is required in patients with any degree of hepatic impairment. AIM To investigate whether hepatic impairment affects linagliptin pharmacokinetics, pharmacodynamics and tolerability. METHOD This open label, parallel group, single centre study enrolled patients with mild (n= 8), moderate (n= 9) or severe (n= 8) hepatic impairment and healthy subjects (n= 8). Groups were matched with regard to age, weight and gender. Primary endpoints were linagliptin exposure following 5 mg linagliptin once daily for 7 days in patients with mild and moderate hepatic impairment vs. healthy subjects or after a single 5 mg dose for patients with severe hepatic impairment vs. healthy subjects. RESULTS In mild hepatic impairment, steady‐state linagliptin exposure was slightly lower than in healthy subjects [AUCτ,ss geometric mean ratio (GMR) 75.5%, 90% confidence interval (CI) 61.6%, 92.5%, and Cmax,ss GMR 64.4%, 90% CI 43.2%, 96.0%]. Exposure also tended to be lower in moderate hepatic impairment (AUCτ,ss GMR 85.5%, 90% CI 70.2%, 104.2% and Cmax,ss GMR 92.3%, 90% CI 62.8%, 135.6%). After a single dose, AUC(0,24 h) in patients with severe hepatic impairment was similar to that in healthy subjects (GMR 100.4%, 90% CI 75.0%, 134.3%) and Cmax was lower (GMR 77.0%, 90% CI 44.9%, 132.3%). Accumulation based on AUC or Cmax and renal excretion of unchanged linagliptin (≤7%) were comparable across groups. Median plasma DPP‐4 inhibition was similar in healthy subjects (91%), and patients with mild (90%) and moderate (89%) hepatic impairment at steady‐state trough concentrations, and in patients with severe hepatic impairment 24 h after a single dose (84%). Linagliptin was well tolerated. CONCLUSION Mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing compared with normal hepatic function. Dose adjustment with linagliptin is not required in patients with hepatic impairment.

Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus

“…The PK characteristics of all DPP-4 inhibitors have been assessed in patients with CLD. Whereas vildagliptin [39] , saxagliptin [43] and linagliptin [47] have been evaluated after a single oral dose in patients with mild, moderate or severe HI, sitagliptin [26] and alogliptin [50,51] have only been tested in patients with moderate HI, according to Child-Pugh staging. Regarding GLP-1 receptor agonists, only liraglutide has been evaluated in a specifically designed study in patients with mild, moderate and severe HI [57] .…”

“…Steady-state PK parameters measured after 7-day linagliptin administration were generally comparable between patients with mild and moderate HI and healthy subjects, with only a slight trend to lower linagliptin exposure (Table 4). The relatively lower linagliptin exposure in patients with HI may appear somewhat surprising and several explanations may be proposed for this observation as discussed by the Authors [47] . The most likely reason for the absence of increased exposure to linagliptin despite HI may be related to the PK and PD properties of the drug.…”

“…In the only study where a DPP-4 inhibitor (5 mg linagliptin) was administered once daily for 7 days in patients with mild and moderate HI, the DPP-4 inhibitor was well tolerated [47] . Only one case report described a probable linagliptin-induced liver toxicity, but again caution is required when interpreting this event [49] .…”

“…An open label, parallel group, study enrolled patients with mild, moderate or severe CLD and healthy subjects to investigate whether HI affects linagliptin PK, PD and tolerability [47] .…”

“…Thus, mild, moderate or severe HI did not result in any increase in linagliptin exposure after single and multiple dosing compared with normal hepatic function, and did not influence the effect of linagliptin 5 mg on DPP-4 inhibition. The conclusion was that dose adjustment with linagliptin is not required in patients with HI [47] .…”