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Breast Cancer

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01-01-2021 | Breast Cancer | Original Article

Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant

Authors: Kate R. Secombe, Imogen A. Ball, Joseph Shirren, Anthony D. Wignall, Dorothy M. Keefe, Joanne M. Bowen

Published in: Breast Cancer | Issue 1/2021

Abstract

Background

Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor, approved by the FDA for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the most frequently observed adverse event with tyrosine kinase inhibitor therapy. In this study, we developed a reproducible model for neratinib-induced diarrhea in male and female rats.

Methods

At first, male rats were treated with neratinib at 15, 30 or 50 mg/kg or vehicle control via oral gavage for 28 days (total n = 12). Secondly, we compared outcomes of male (n = 7) and female (n = 8) rats, treated with 50 mg/kg neratinib.

Results

Rats treated with a 50 mg/kg daily dose of neratinib had a reproducible and clinically relevant level of diarrhea and therefore was confirmed as an appropriate dose. Male rats treated with neratinib had significant changes to their gut microbiome. This included neratinib-induced increases in Ruminococcaceae (P = 0.0023) and Oscillospira (P = 0.026), and decreases in Blautia (P = 0.0002). On average, female rats experienced more significant neratinib-induced diarrhea (mean grade 1.526) compared with male rats (mean grade 1.182) (P < 0.0001). Neratinib caused a reduction in percentage weight gain after 28 days of treatment in females (P = 0.0018) compared with vehicle controls. Females and males both showed instances of villus atrophy and fusion, most severely in the distal ileum. Serum neratinib concentration was higher in female rats compared to male rats (P = 0.043).

Conclusions

A reproducible diarrhea model was developed in both female and male rats, which indicated that diarrhea pathogenesis is multifactorial, including anatomical disruption particularly evident in the distal ileum, and alterations in microbial composition.

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Title: Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant
Authors: Kate R. Secombe
Imogen A. Ball
Joseph Shirren
Anthony D. Wignall
Dorothy M. Keefe
Joanne M. Bowen
Publication date: 01-01-2021
Publisher: Springer Japan
Keywords: Breast Cancer
Tyrosine Kinase Inhibitors
Breast Cancer
Diarrhea
Diarrhea
Tyrosine Kinase Inhibitors
Neratinib
Published in: Breast Cancer / Issue 1/2021
Print ISSN: 1340-6868
Electronic ISSN: 1880-4233
DOI: https://doi.org/10.1007/s12282-020-01133-9

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Abstract

Background

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