ArticleBreast cancer (Tokyo, Japan)2021
Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant.
Article in Breast cancer (Tokyo, Japan), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 11 citations in OpenAlex.
- Preclinical and clinical evaluation through serial colonoscopic evaluation of neratinib-induced diarrhea in HER2-positive breast cancer-A pilot study.Physiological reports · 2024Trial
- Blautia luti reduces neratinib-induced diarrhea in a rat model.Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 2025Article
- Development of Novel Neratinib and Docetaxel Core-Loaded and Trastuzumab Surface-Conjugated Nanoparticle for Treatment of HER-2 Positive Breast Cancer.Pharmaceutics · 2025Article
- Nanotechnology Platform for the Delivery of Docetaxel and Tyrosine Kinase Inhibitors for HER2-Positive Breast Cancer Therapy.Pharmaceutical nanotechnology · 2025Article
- Ferroptosis - a potential feature underlying neratinib-induced colonic epithelial injury.Cancer chemotherapy and pharmacology · 2024Article
- Updated perspectives on the contribution of the microbiome to the pathogenesis of mucositis using the MASCC/ISOO framework.Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 2024Review
- Review
- Antibiotic treatment targeting gram negative bacteria prevents neratinib-induced diarrhea in rats.Neoplasia (New York, N.Y.) · 2022Article
- Neratinib causes non-recoverable gut injury and reduces intestinal cytochrome P450 3A enzyme in mice.Toxicology research · 2022Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundNeratinib 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.
methodsAt 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.
resultsRats 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).
conclusionsA 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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