Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs.
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 tre...
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS ONE |
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| author | Michael Guy Andre Teixeira Allison Shrier Carol Meschter James Bolognese Pravin Chaturvedi |
| author_facet | Michael Guy Andre Teixeira Allison Shrier Carol Meschter James Bolognese Pravin Chaturvedi |
| author_sort | Michael Guy |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e159ad4a94b04091899b4d9c8c41de21 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-e159ad4a94b04091899b4d9c8c41de212025-08-20T02:10:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-01191e028276910.1371/journal.pone.0282769Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs.Michael GuyAndre TeixeiraAllison ShrierCarol MeschterJames BolognesePravin ChaturvediTargeted 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0282769&type=printable |
| spellingShingle | Michael Guy Andre Teixeira Allison Shrier Carol Meschter James Bolognese Pravin Chaturvedi Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs. PLoS ONE |
| title | Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs. |
| title_full | Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs. |
| title_fullStr | Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs. |
| title_full_unstemmed | Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs. |
| title_short | Effects of orally administered crofelemer on the incidence and severity of neratinib-induced diarrhea in female dogs. |
| title_sort | effects of orally administered crofelemer on the incidence and severity of neratinib induced diarrhea in female dogs |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0282769&type=printable |
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