title: The concentration-dependent binding of linagliptin (BI 1356) and its implication on efficacy and safety.
abstract: OBJECTIVE
  Linagliptin (BI 1356) is a dipeptidyl peptidase-4 (DPP-4) inhibitor for treatment of Type 2 diabetes which recently gained approval in the US, Europe, and Japan. Linagliptin showed nonlinear pharmacokinetics after intravenous and oral administration, which is due to a concentration-dependent protein binding of linagliptin to its target enzyme DPP-4. The aim of this analysis was to investigate this target-mediated binding of linagliptin and its implication on efficacy and safety.
  
  
  METHODS
  Pharmacokinetic modeling and simulations were performed using a two-compartment model with concentration-dependent binding in the central and in one peripheral compartment. The optimum therapeutic dose with minimal off-target side effects was simulated assuming that an antidiabetic effect of linagliptin was due to the linagliptin concentration bound to DPP-4 and that off-target side effects were related to free linagliptin.
  
  
  RESULTS
  The difference between steady state AUCs of specifically bound and free linagliptin was maximized at oral doses of 2 - 5 mg. Since plasma DPP-4 inhibition increased slightly from 2.5 to 10 mg, pharmacokinetic simulations and the pharmacodynamic measurements taken together suggest that 5 mg linagliptin could be considered an optimum dose. Simulations with missed doses and additional doses at steady state showed the effect on DPP-4 bound linagliptin and change in DPP-4 inhibition was minimal after missing one 5 mg oral dose of linagliptin while two doses of 5 mg linagliptin resulted in a less than proportional increase of steady state AUC of free linagliptin.
  
  
  CONCLUSIONS
  Results from modeling and simulation support a stable antidiabetic effect of linagliptin over 24 h at steady state and further indicate a low risk for off-target side effects.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Sasiporn
authors.initials: S
authors.lastname: Wright
authors.forename: Rajendra P
authors.initials: RP
authors.lastname: Singh
authors.forename: Silke
authors.initials: S
authors.lastname: Retlich
authors.forename: Ulrike
authors.initials: U
authors.lastname: Graefe-Mody
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
mesh_terms: D001798:Blood Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D000069476:Linagliptin; D008954:Models, Biological; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D001798:Blood Proteins; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D018819:Dipeptidyl Peptidase 4