Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs

Abstract Management guidelines for cancer therapy-related diarrhea (CTD) should be revised because newer targeted therapies have increased CTD burden, with high incidence and/or severity of diarrhea for some agents that inhibit epidermal growth factor receptor and receptor tyrosine kinases. Neratinib, a pan-HER tyrosine kinase inhibitor, approved for breast cancer treatment, causes severe diarrhea in >95% of patients. Crofelemer, a novel intestinal chloride ion channel modulator, is an approved antidiarrheal for patients with HIV receiving antiretroviral therapy. The objective of this study was to evaluate the effectiveness of crofelemer prophylaxis in reducing the incidence and severity of neratinib-induced diarrhea without loperamide in dogs. Female dogs received neratinib orally daily concomitantly with either matching placebo tablets (CTR) or crofelemer 125 mg delayed-release tablet two or four times/day (BID or QID) for 28 consecutive days. At the end of treatment, 37.5%, 75%, and 87.5% of the CTR, BID, and QID dogs were ‘responders’ defined as ≤7 loose/watery stools/week for at least 2 of 4 weeks (p<0.05). The average number of watery stools per week was 9, 6, and 6 in the CTR, BID, and QID groups, respectively (p<0.05). The average number of weeks with no loose/watery stools was 1.3, 2.1, and 2.3 for the CTR, BID, and QID groups, respectively (p<0.05). The weekly mean fecal scores and stool consistency were 5.1, 3.9, and 4.1 for the CTR, BID, and QID groups (p<0.05). In this 28-day preclinical study, crofelemer prophylaxis without loperamide reduced the incidence and severity of neratinib-associated diarrhea in female dogs by 30%. Ethical Compliance All procedures performed in studies involving canine participants were in accordance with the ethical standards of the institutional and/or national research committee and applicable Institutional Animal Care and Use Committee (IACUC).