Pharmacokinetics of linagliptin in subjects with hepatic impairment
Article first published online: 11 JUN 2012
© 2012 Boehringer Ingelheim. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 74, Issue 1, pages 75–85, July 2012
How to Cite
Graefe-Mody, U., Rose, P., Retlich, S., Ring, A., Waldhauser, L., Cinca, R. and Woerle, H.-J. (2012), Pharmacokinetics of linagliptin in subjects with hepatic impairment. British Journal of Clinical Pharmacology, 74: 75–85. doi: 10.1111/j.1365-2125.2012.04173.x
- Issue published online: 11 JUN 2012
- Article first published online: 11 JUN 2012
- Accepted manuscript online: 13 JAN 2012 09:44AM EST
- Received; 10 May 2011; Accepted; 25 December 2011; Accepted Article Published Online; 13 January 2012
- DPP-4 inhibitor;
- hepatic impairment;
- type 2 diabetes mellitus
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.