Abstract Rationale Ferrets have similar airway anatomy and physiology to humans and therefore provide major advantages for modeling airway diseases, including idiopathic pulmonary fibrosis (IPF). We and others have demonstrated that ferrets exposed to bleomycin (BLM) exhibit persistent fibrotic lung disease and bronchiolization of the distal airway spaces, hallmarks of human IPF. Nintedanib (OFEV) is one of the only two FDA-approved antifibrotic drugs for IPF patient. In a pilot study, we tested nintedanib on BLM-induced IPF-like injury in ferrets. Methods Sex-matched adult ferrets were exposed to a single dose of 5 U/kg BLM intratracheally via micro-aerosolization in a length-specific manner. 60mg/kg nintedanib (n = 6) or vehicle (n = 4) three times daily (twice on weekend days) was provided orally. Body weight, lung µCT and lung function (by flexiVent) were measured at baseline, 3 and 6 week post BLM exposure before ferrets were euthanized. Lungs were collected for evaluation of gross pathology and histological analysis. Results Pharmacokinetic study of both single dose (30 and 60mg/kg) and steady state indicated extremely fast and variable metabolism of nintedanib in ferrets. We used 60mg/kg three times daily (t.i.d.) to maximize the possibility of maintaining a steady state of 20ng/ml in blood. Weight loss at the end of the study was not significantly different between ninedanib (14±2%) and vehicle (6±6%) groups (P = 0.2619 by Mann-Whitney test). Both groups exhibited fibrotic lung injury at 3 and 6 wk post BLM as indicated by a) patchy opacification and consolidation by µCT; b) lung restriction including downward shift of pressure-volume loops, decreased inspiratory capacity (27±9 vehicle vs 33±5% nintedanib) and compliance (22±8 vehicle vs 31±4% nintedanib) by flexiVent measurements; c) subpleural fibrotic lobulation and retraction by gross pathology; and d) histopathology including increased injured lung area (22±6 vehicle vs 20±2% nintedanib), Ashcroft score (4±1 vehicle vs 5±0 nintedanib), and other injury scores. However, there was no significant difference between nintedanib and vehicle groups. Conclusions In this pilot study, 60mg/kg nintedanib t.i.d did not improve the progression of BLM-induced fibrotic injury in ferrets, as indicated by physiology or histopathology. However, higher dose may be required due to the fast metabolism of nintedanib in ferrets. Further studies should evaluate higher doses over longer treatment periods. This abstract is funded by: NIH
Li et al. (Fri,) studied this question.
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