Pharmacokinetics of linagliptin in subjects with 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 [AUCt,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 (AUCt,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.