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

• Published in: PloS one Vol. 19; no. 1; p. e0282769
• Main Authors: Guy, Michael, Teixeira, Andre, Shrier, Allison, Meschter, Carol, Bolognese, James, Chaturvedi, Pravin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.01.2024; Public Library of Science (PLoS)
• Subjects: Analysis; Antiretroviral agents; Antiretroviral therapy; Biology and Life Sciences; Breast cancer; Cancer; Cancer therapies; Care and treatment; Chemotherapy; Chloride; Chloride ions; Constipation; Crofelemer; Dehydration; Diarrhea; Disease prevention; Dogs; Dosage and administration; Drug approval; Drug dosages; Drug therapy; Electrolytes; Epidermal growth factor; FDA approval; Feces; Females; Growth factors; Health aspects; Highly active antiretroviral therapy; HIV patients; Ion channels; Irritable bowel syndrome; Kinases; Loperamide; Medicine and Health Sciences; Oral administration; Patient outcomes; Pertuzumab; Physical Sciences; Pilot projects; Prophylaxis; Receptors; Tablets; Tumors; Tyrosine; United States; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0282769

Targeted therapies have increased cancer therapy-related diarrhea (CTD) burden, with high incidence and/or severity of diarrhea for some agents that inhibit epidermal growth factor receptor and receptor tyrosine kinases. Neratinib is a pan-HER tyrosine kinase inhibitor approved for breast cancer treatment and causes severe diarrhea in >95% of patients. Crofelemer, a novel intestinal chloride ion channel modulator, is an approved antidiarrheal drug for symptomatic relief of noninfectious diarrhea in patients with HIV/AIDS receiving antiretroviral therapy. The objective of this study was to evaluate the effectiveness of crofelemer prophylaxis in reducing the incidence /severity of neratinib-induced diarrhea without concomitant administration of loperamide in female beagle dogs. A pilot study using 3 dogs determined a maximum daily tolerated dose of neratinib was between 40 and 80 mg; this dose would induce a consistent incidence/severity of diarrhea without risking severe dehydration. In the definitive study, 24 female beagle dogs (8/group) received neratinib once daily and placebo capsules (CTR) four times/day, or neratinib once daily and crofelemer 125 mg delayed-release tablets given two times (BID), or neratinib once daily and crofelemer 125 mg delayed-release tablets given four times per day (QID). Fecal scores were collected twice daily using an established canine stool scoring scale called the Purina Fecal Scoring (PFS) System. After 28 days, using analysis of covariance (ANCOVA), dogs in the CTR group had a significantly higher average number of weekly loose/watery stools (PFS of 6 or 7) when compared to either crofelemer BID (8.71±2.2 vs. 5.96±2.2, p = 0.028) or crofelemer QID (8.70±2.2 vs. 5.74±2.2, p = 0.022) treatment groups. The average number of weekly loose/watery stools were not different between the crofelemer BID and QID treatment groups (p = 0.84). This study showed that crofelemer prophylaxis reduced the incidence/severity of neratinib-associated diarrhea in female beagle dogs without the need for any loperamide administration.