Clinical Pharmacokinetics and Pharmacodynamics of Linagliptin

Linagliptin is an orally active small-molecule inhibitor of dipeptidyl peptidase (DPP)-4, which was first licensed in the US, Europe, Japan and other territories in 2011 to improve glycaemic control in adults with type 2 diabetes mellitus. Linagliptin is the first and thus far the only DPP-4 inhibit...

Full description

Saved in:
Bibliographic Details
Published in:Clinical pharmacokinetics 2012-07, Vol.51 (7), p.411-427
Main Authors: Graefe-Mody, Ulrike, Retlich, Silke, Friedrich, Christian
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Diabetes Mellitus, Type 2 - metabolism
Dipeptidyl-Peptidase IV Inhibitors - pharmacokinetics
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
Drug Interactions
General pharmacology
Humans
Internal Medicine
Linagliptin
Medical sciences
Medicine
Medicine & Public Health
Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions
Pharmacology. Drug treatments
Pharmacology/Toxicology
Pharmacotherapy
Purines - pharmacokinetics
Purines - pharmacology
Quinazolines - pharmacokinetics
Quinazolines - pharmacology
Review Article
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Linagliptin is an orally active small-molecule inhibitor of dipeptidyl peptidase (DPP)-4, which was first licensed in the US, Europe, Japan and other territories in 2011 to improve glycaemic control in adults with type 2 diabetes mellitus. Linagliptin is the first and thus far the only DPP-4 inhibitor, and oral anti-hyperglycaemic drug in general, to be approved as a single-strength once-daily dose (5 mg). Compared with other available DPP-4 inhibitors, linagliptin has a unique pharmacokinetic/pharmacodynamic profile that is characterized by target-mediated nonlinear pharmacokinetics, concentration-dependent protein binding, minimal renal clearance and no requirements for dose adjustment for any intrinsic or extrinsic factor. After single or multiple oral doses of 1–10 mg, linagliptin displays less than dose-proportional increases in maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC). Linagliptin is rapidly absorbed after oral administration, with C max occurring after approximately 90 minutes, and reaches steady-state concentrations within 4 days. With the therapeutic dose, steady-state C max (11–12nmol/L) and AUC (∼150nmol · h/L) are approximately 1.3-fold greater than after a single dose, indicating little drug accumulation with repeat dosing. Linagliptin exhibits concentration-dependent protein binding in human plasma in vitro (99% at 1 nmol/L to 75–89% at >30 nmol/L) and has a large apparent volume of distribution, demonstrating extensive distribution into tissues. The nonlinear pharmacokinetics of linagliptin are best described by a two-compartmental model that incorporates target-mediated drug disposition resulting from high-affinity, saturable binding to DPP-4. The oral bioavailability of linagliptin estimated with this model is approximately 30%. Linagliptin has a long terminal half-life (>100 hours); however, its accumulation half-life is much shorter (approximately 10 hours), accounting for the rapid attainment of steady state. The majority of linagliptin is eliminated as parent compound, demonstrating that metabolism plays a minor role in the overall pharmacokinetics in humans. The main, pharmacologically inactive S-3-hydroxypiperidinyl metabolite accounted for approximately 17% of the total drug-related compounds in plasma. Linagliptin is eliminated primarily in faeces, with only around 5% of the oral therapeutic dose excreted in the urine at steady state. Linagliptin potently inhibits DPP-4 (inhibit
ISSN:0312-5963
1179-1926
DOI:10.2165/11630900-000000000-00000