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Updated: May 22, 2026

Bio-layer Interferometry for Measuring Kinetics of Protein-protein Interactions and Allosteric Ligand Effects
Published on: February 18, 2014
The concentration-dependent binding of linagliptin (BI 1356) and its implication on efficacy and safety
Sasiporn Wright1, Rajendra P Singh, Silke Retlich
1Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
Objectives:
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.
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