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Open Access 01-07-2015 | Original Research Article

Population Pharmacokinetics and Pharmacodynamics of Linagliptin in Patients with Type 2 Diabetes Mellitus

Authors: Silke Retlich, Vincent Duval, Ulrike Graefe-Mody, Christian Friedrich, Sanjay Patel, Ulrich Jaehde, Alexander Staab

Published in: Clinical Pharmacokinetics | Issue 7/2015

Abstract

Background and Objectives

Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor, used to treat type 2 diabetes mellitus (T2DM). Population pharmacokinetic and pharmacodynamic analyses were performed to characterize the impact of clinically relevant intrinsic/extrinsic factors (covariates) on linagliptin exposure and DPP-4 inhibition in patients with T2DM.

Methods

Linagliptin plasma concentrations and DPP-4 activities were obtained from four studies (two phase 1, two phase 2b). Non-linear mixed-effects modelling techniques were implemented using NONMEM software. The covariates that were studied comprised demographic information and laboratory values, including liver enzyme levels and creatinine clearance, as well as study-related factors such as metformin co-treatment. Covariate effects on parameters describing the pharmacokinetics and pharmacokinetic/pharmacodynamic relationship were investigated using stepwise forward inclusion/backward elimination.

Results

The pharmacokinetic analysis included 6,907 measurements of plasma linagliptin concentrations from 462 patients; the pharmacokinetic/pharmacodynamic analysis included 9,674 measurements of plasma DPP-4 activity and linagliptin plasma concentrations from 607 patients. The non-linear pharmacokinetics were described by a target-mediated drug disposition model accounting for the concentration-dependent binding of linagliptin to its target, DPP-4. The difference in exposure between the 5th and 95th percentiles of the covariate distributions and median was <20 % for each single covariate. Likewise, the impact of the covariates on both the half-maximum effect (EC₅₀) and the concentration leading to 80 % DPP-4 inhibition was <20 %.

Conclusion

These analyses show that the investigated factors do not alter the pharmacokinetics and DPP-4 inhibitory activity of linagliptin to a clinically relevant extent and that dose adjustment is not necessary on the basis of factors including age, sex and weight.

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Title: Population Pharmacokinetics and Pharmacodynamics of Linagliptin in Patients with Type 2 Diabetes Mellitus
Authors: Silke Retlich
Vincent Duval
Ulrike Graefe-Mody
Christian Friedrich
Sanjay Patel
Ulrich Jaehde
Alexander Staab
Publication date: 01-07-2015
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 7/2015
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-014-0232-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Population Pharmacokinetics and Pharmacodynamics of Linagliptin in Patients with Type 2 Diabetes Mellitus

Abstract

Background and Objectives

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background and Objectives

Methods

Results

Conclusion

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