Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that was recently approved by the FDA for the extended adjuvant treatment of HER2+ breast cancer and is being evaluated clinically in other HER2 related cancers. Diarrhoea is the most frequently observed adverse event with this agent. Our previously developed rat model for neratinib-induced diarrhoea has indicated that the diarrhoea pathogenesis is multifactorial, including anatomical disruption and inflammation particularly evident in the distal small intestine. This study aimed to use this model to evaluate the corticosteroid budesonide, as an intervention for reducing neratinib-induced diarrhoea in rats.
As part of a larger study, male Albino Wistar rats (n=48) were treated daily with 50 mg/kg neratinib and 1 mg/kg budesonide or vehicle control (5% DSMO / 1% carboxymethyl cellulose). Budesonide and neratinib were orally gavaged 2 hours apart, with animals killed after either 14 or 28 days of treatment. Diarrhoea was scored twice daily using a 4-point grading system (0-3). Histopathological damage within the gastrointestinal tract was assessed using an established injury score. Inflammation was measured by myeloperoxidase assay and multiplex cytokine/chemokine ELISA.
Budesonide significantly decreased the mean number of days with moderate (grade 2) neratinib-induced diarrhoea (10.0±1) compared to control (15.75±2.7) (p=0.027), and significantly reduced histopathological injury scores in both the ileum and colon (p <0.0001). In the ileum, budesonide treated rats had lower myeloperoxidase activity (1.28±0.32 U/mg) compared to control (7.47±1.25 U/mg) at 14 days, and significantly increased anti-inflammatory IL-4 concentration (p=0.01).
Budesonide successfully decreased number of days with diarrhoea, reduced histopathological injury, and mitigated inflammation. Protection appears to be via upregulation of anti-inflammatory cytokine production and decreased innate immune cell infiltration. These findings warrant further investigation in clinical trials.