Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients

Diabetes Obes Metab. 2009 Aug;11(8):786-94. doi: 10.1111/j.1463-1326.2009.01046.x. Epub 2009 May 19.


Aims: To investigate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of multiple oral doses of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (BI 1356) in patients with type 2 diabetes mellitus.

Methods: Forty-seven male type 2 diabetic patients received linagliptin 1, 2.5, 5 or 10 mg, or placebo, once daily for 12 days.

Results: Linagliptin exposure [area under the plasma concentration-time curve and maximum plasma concentration (Cmax)] increased less than proportionally with dose. Accumulation half-life was short (8.6-23.9 h), resulting in rapid attainment of steady state (2-5 days) and little accumulation (range: 1.18-2.03). The long terminal half-life (113-131 h) led to a sustained inhibition of DPP-4 activity. Renal excretion was below 1% on day 1 in all dose groups. Inhibition of plasma DPP-4 activity correlated well with linagliptin plasma concentrations, resulting in DPP-4 inhibition >90% in the two highest dose groups; even 24 h postdose, DPP-4 inhibition was >80%. Following an oral glucose tolerance test, 24 h after the last dose, statistically significant reductions of glucose excursions were observed with linagliptin (2.5, 5 and 10 mg doses) compared with placebo. Linagliptin was well tolerated. The frequency of adverse events (AEs) was not higher with linagliptin (54%) than with placebo (75%). No serious AEs and no episodes of hypoglycaemia were reported.

Conclusions: In type 2 diabetic patients, multiple rising doses of linagliptin were well tolerated and resulted in significant improvements of glucose parameters. Together with the favourable pharmacokinetics, these results confirm the unique profile of linagliptin in the DPP-4 inhibitor class.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Area Under Curve
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl Peptidase 4 / blood
  • Dipeptidyl-Peptidase IV Inhibitors / administration & dosage*
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Half-Life
  • Humans
  • Linagliptin
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Purines / administration & dosage
  • Purines / adverse effects*
  • Purines / pharmacokinetics*
  • Quinazolines / administration & dosage
  • Quinazolines / adverse effects*
  • Quinazolines / pharmacokinetics*
  • Young Adult


  • Dipeptidyl-Peptidase IV Inhibitors
  • Purines
  • Quinazolines
  • Linagliptin
  • Dipeptidyl Peptidase 4