Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin

Aim: This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily non-renal route of excretion, in subjects with type 2 diabetes mellitus (T2DM). Methods: Linagliptin pharmacokinetics was studied under single-dose and steady-state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end-stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM). Results: Renal excretion of unchanged linagliptin was <7% in all groups. Under single-dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration-time profiles. These showed a similar decline and almost identical plasma concentrations 24 h postdosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20-60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady-state AUC and C(max) values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half-life of linagliptin ranged from 14-15 h in subjects with normal renal function to 18 h in severe renal impairment. Only a weak correlation (r(2) = 0.18) was seen between creatinine clearance and steady-state exposure. Conclusions: Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM.