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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 9/2019

Open Access 01-09-2019 | Idiopathic Pulmonary Fibrosis | Review Article

Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib

Authors: Sven Wind, Ulrike Schmid, Matthias Freiwald, Kristell Marzin, Ralf Lotz, Thomas Ebner, Peter Stopfer, Claudia Dallinger

Published in: Clinical Pharmacokinetics | Issue 9/2019

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Abstract

Nintedanib is an oral, small-molecule tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis and patients with advanced non-small cell cancer of adenocarcinoma tumour histology. Nintedanib competitively binds to the kinase domains of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF). Studies in healthy volunteers and in patients with advanced cancer have shown that nintedanib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of nintedanib are reached approximately 2–4 h after oral administration and thereafter decline at least bi-exponentially. Over the investigated dose range of 50–450 mg once daily and 150–300 mg twice daily, nintedanib exposure increases are dose proportional. Nintedanib is metabolised via hydrolytic ester cleavage, resulting in the formation of the free acid moiety that is subsequently glucuronidated and excreted in the faeces. Less than 1% of drug-related radioactivity is eliminated in urine. The terminal elimination half-life of nintedanib is about 10–15 h. Accumulation after repeated twice-daily dosing is negligible. Sex and renal function have no influence on nintedanib pharmacokinetics, while effects of ethnicity, low body weight, older age and smoking are within the inter-patient variability range of nintedanib exposure and no dose adjustments are required. Administration of nintedanib in patients with moderate or severe hepatic impairment is not recommended, and patients with mild hepatic impairment should be monitored closely and the dose adjusted accordingly. Nintedanib has a low potential for drug–drug interactions, especially with drugs metabolised by cytochrome P450 enzymes. Concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of nintedanib. At an investigated dose of 200 mg twice daily, nintedanib does not have proarrhythmic potential.
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Metadata
Title
Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib
Authors
Sven Wind
Ulrike Schmid
Matthias Freiwald
Kristell Marzin
Ralf Lotz
Thomas Ebner
Peter Stopfer
Claudia Dallinger
Publication date
01-09-2019
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 9/2019
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-019-00766-0

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