Understanding of Pharmacokinetics and Exposure Drives use of Nintedanib as a Positive Control Reference Item in a Rat Model of Bleomycin-Induced Fibrosis

Introduction: The bleomycin model of lung fibrosis is widely used to evaluate the efficacy of novel anti-fibrotic drugs and nintedanib is an clinically relevant reference control compound. The objectives of this study were to use pharmacokinetic (PK) modelling to predict a nintedanib dose sufficient to provide efficacy in a rat model of repetitive bleomycin dosing and then demonstrate the anti-fibrotic reproducibility of the efficacious nintedanib dose. Methods: Studies were performed in male rats. Pharmacokinetic parameters were determined following administration of nintedanib at 60 mg/kg (QD or BID) and free drug calculations were based on rat lung and plasma protein binding studies. For fibrosis studies, bleomycin was administered to the lung on five occasions; nintedanib or vehicle were administered at 60 mg/kg QD or BID (Day -1 to Day 27). Fibrosis was assessed using the hydroxyproline assay (HP) and modified Ashcroft Score on collagen-stained lung sections. Results: PK modelling of free nintedanib concentrations, relative to cellular potency, suggested that 60 mg/kg BID gave 40-70% target coverage between dose occasions compared to 60 mg/kg QD which gave only 10% target coverage at Ctrough. Consistent with the PK modelling, nintedanib 60 mg/kg BID significantly reduced HP and the fibrosis score in four independent studies while 60 mg/kg, QD, was not consistently anti-fibrotic. Conclusion: An understanding of PK is vital to optimise dose for efficacy studies and nintedanib 60 mg/kg BID is a suitable control reference item in a repetitive bleomycin model of lung fibrosis in the rat.