Anti-fibrotic effect and in vivo target engagement of Nintedanib administered by oral gavage or by a medicated diet in a bleomycin lung fibrosis model in the rat

Introduction or background: Nintedanib is an approved orally available, small-molecule anti-fibrotic multi-kinase inhibitor with selectivity for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptors. Aims and objectives: To verify in a rat model of lung fibrosis: 1) the efficacy profile of Nintedanib administered by oral gavage and by chow supplementation; 2) in vivo lung target engagement to confirm adequate Nintedanib exposure in both conditions. Methods: Male SD rats were intratracheally injected with 1 U/kg Bleomycin (BLM) on day 0 and day 4. Parallel groups of animals received Nintedanib by oral gavage (100 mg/kg/day) or through a medicated chow (1.6 g Nintedanib/kg of diet) from day 7 post-BLM and sacrificed 3 weeks later. To assess fibrosis, Ashcroft scores, automated high-resolution imaging histomorphometric analysis and lung markers (procollagen-I, WISP-1 and VEGF) were assessed. Results: Nintedanib administered by oral gavage and by medicated chow did significantly reduce lung weight, procollagen-I, WISP-1 and fibrosis scores (Ashcroft and automated scores). Nintedanib-treated animals expressed higher lung levels of VEGF (≥ 3-fold, p<0.05), respect to controls. Conclusions. Efficacy of Nintedanib administered by oral gavage or supplement for chow did show similar anti-fibrotic profile. Interestingly, in both regimen conditions, Nintedanib significantly increased VEGF levels into the lung. This latter finding, as proof of target engagement, may likely suggest the activation of a compensatory reflex to the blockade of VEGF receptors.