The effect of nintedanib compared to pirfenidone on proliferation of lung fibroblasts from patients with IPF

Abstract

Background: Nintedanib and pirfenidone were recently authorized for the treatment of idiopathic pulmonary fibrosis (IPF) in the US and EU. Nintedanib is a tyrosine kinase inhibitors targeting also PDGFRα/β, FGFR1-3 and VEGFR1-3. In contrast, the molecular target of pirfenidone is currently unknown. Lung fibroblast proliferation is accepted as a fundamental mechanism in the pathogenesis of IPF. Aim: To determine the effect of nintedanib and pirfenidone on the proliferation of PDGF- or serum-stimulated human lung fibroblasts. Methods: Lung fibroblasts from patients with IPF (IPF-HLF) were incubated with nintedanib (0.32 nM - 1 µM) or pirfenidone (1 µM - 1.6 mM) for 30 min. Subsequently, the cells were stimulated with PDGF (50 ng/mL) or fetal bovine serum (FBS) 1% and cell proliferation was assessed by BrdU assay after 92 h. Results: Nintedanib reduced the increase in IPF-HLF proliferation in a concentration-dependent manner. At a concentration of 70 nM, which may be achieved after standard dosing of nintedanib (150 mg bid) in patients, proliferation of IPF-HLF was inhibited by 65% and 22% for PDGF and FCS, respectively. Pirfenidone showed only very weak inhibitory activity. At concentrations of 80-100 µM, which may be achieved in patients after standard dosing (801 mg tid), no inhibitory activity was observed on PDGF- or FCS-stimulated proliferation. Conclusion: Our data demonstrate that nintedanib but not pirfenidone inhibits the proliferative fibrotic effect at concentrations relevant for clinical use. This may contribute to the clinically documented anti-fibrotic activity of nintedanib in patients with IPF resulting in a slowing of disease progression.