COrrelating plasma Nintedanib COncentRations with efficacy and toxicity in patients with interstitial lung DIseAse

Tyrosine kinase inhibitors (TKIs) are one of the cornerstones in the treatment
of various diseases. TKIs cause cell-cycle arrest, induce apoptosis, inhibit
angiogenesis, and modulate cell immunity by specifically inhibiting cellular
signal transduction through blocking dysregulated protein kinases. These
characteristics make them excellent candidates for treating uncontrolled cell
growth or activity. The vast majority of TKIs is therefor given as targeted
anti-cancer agent for multiple types of malignancies. Nintedanib however, is an
oral TKI registered for both metastatic non-small cell lung cancer and as
first-line treatment for idiopathic pulmonary fibrosis (IPF) and systemic
sclerosis-associated interstitial lung disease (SSc-ILD), rare and fatal
diffuse parenchymal lung diseases. Compared to placebo, nintedanib (Ofev ®)
reduced the decline in lung function (forced vital capacity; FVC) with 100 ml
(> 50%) annually, and possibly the rate of exacerbations in patients with IPF.
For SSc-ILD, FVC decline was reduced with 41 ml (44%) per year. This year, the
U.S. Food & Drug Administration approved nintedanib for other chronic
progressive fibrotic ILD, making it the first and sole treatment of this
disease class. This decision was made after the INBUILD trial showed an overall
benefit of more than 100 ml (57%) reduction in FVC decline in patients with
symptoms, radiographic evidence of fibrosis and decline in lung function, as
seen with progressive fibrotic ILD. The indication of nintedanib as
anti-fibrotic drug has hence been enlarged significantly.
Besides beneficial effects, nintedanib causes (severe) toxicity; diarrhoea (>
60%), nausea (> 22%), vomiting (> 12%) and elevated liver enzymes. More than
30% of patients experienced serious adverse events during treatment, often
leading to treatment discontinuation, thereby impacting outcomes for patients.
To further optimize this treatment, thorough research is required to establish
possible plasma trough concentrations for efficacy and toxicity. Nevertheless,
knowledge of the meaning of pharmacokinetic (PK) parameters in ILD patients
treated with nintedanib is limited.
Additionally, the interpatient variability of nintedanib is moderate to high
(coefficient of variation of 40-80%) and is influenced by multiple factors;
ethnicity, body weights, smoking behaviour, and age. Nintedanib*s
bioavailability is 4.7% and it is metabolized by CYP3A4 for 5%. The impact of
other variables e.g. comedication, genetics, or food has yet to be established.

To further research nintedanib PK and correlate them with clinical parameters
and toxicity. Results could be used to optimize treatment of nintedanib in the
future by dose individualization based on patient*s characteristics or
therapeutic drug monitoring; adjusting a patients drug dose based on
measurements of drug plasma concentrations.

Prospective cohort study, in which blood is withdrawn and a questionnaire has
to be filled in at every scheduled hospital visit during treatment with
nintedanib.

In this study,extra blood withdrawal will take place during the whole treatment
with nintedanib. The first time, one extra blood sample will be taken for
genetic analysis additionally to the sample taken for nintedanib plasma
concentration analysis.The risk of blood withdrawal by a venous puncture for
study purposes is minimal, especially when it is combined with regular
diagnostic blood withdrawal (which we expect to achieve in the majority of
cases). Moreover, patients are asked to fill in a questionnaire every visit.
There are no risks herewith.