Nintedanib exposure response relationship in patients with interstitial lung disease
Summary
Introduction
Interstitial lung disease (ILD) is a progressive fibrotic lung disease and is treated with nintedanib, a tyrosine
kinase inhibitor (TKI). Although very effective in reducing disease progression, dose limiting toxicities
occur in >30% of the patients, which might lead to loss of efficacy. Additionally, nintedanib
pharmacokinetics (PK) shows high heterogeneity among individuals. In this research, a population PK
model for nintedanib was developed to test covariates and correlate exposure to efficacy and toxicity.
Methods
Data was derived from real-life studies, performed at the Erasmus Medical Centre (EMC) Cancer institute
and was analyzed using non-linear mixed-effects modeling (NONMEM). With the final model, a covariate
analysis was performed. Nintedanib exposure was correlated to efficacy and toxicity using linear mixed
effect models (LMEM) and Cox proportional-hazard analysis.
Results
In total, 923 samples from 95 patients were included in the analysis. Nintedanib PK was best described
with a one-compartment model with first-order absorption, first order elimination, absorption lag time
and inter-individual variability (IIV) on clearance. LMEM found a significant correlation between
nintedanib exposure and diffusion capacity of the lung for carbon monoxide (DLCO) and forced vital
capacity (FVC). Cox proportional-hazard univariate analysis did not find a correlation between nintedanib
exposure and occurrence of toxicity.
Conclusion
Patients with increased nintedanib exposure have a reduced DLCO and FVC decline. The DLCO is a
convenient and efficient marker for nintedanib efficacy and disease progression. For efficacious
treatment, it is important to expose patients to adequate nintedanib concentrations with a therapeutic
dose of 150 mg bid. This is safe, as increased exposure is not correlated with toxicity.