Background: Dacomitinib is a new irreversible pan-HER tyrosine kinase inhibitor currently in clinical trials for the treatment of advanced cancers. Patient oncology results have been promising, however dacomitinib use has been hindered by significant diarrhoea. The underlying mechanism(s) of dacomitinib-induced diarrhoea are unknown, but have been hypothesized to be due to secretory mechanisms within the gut. Crofelemer is a natural compound extracted from the stem bark latex croton lechleri tree. It is known to have antisecretory activity due to its dual inhibitory action on CFTR and CaCC and is currently used clinically to treat diarrhoea associated with AIDS antiretroviral medication.
Aim: To determine if crofelemer is an effective inhibitor of dacomitinib-induced diarrhoea
Methods: Male Wistar rats (n=36) received 7.5mg/kg dacomitinib and either 10mg/kg, 25mg/kg or 50mg/kg crofelemer via daily oral gavage for 21 days. Diarrhoea was graded 2xdaily using a validated diarrhoeal grading system. Rats were killed after 21 days and the entire gastrointestinal tract removed. Samples of distal colon were mounted in ussing chambers to measure Isc as an indicator of chloride secretion and routine histopathological analysis was conducted along the gastrointestinal tract.
Results: In the current administrative schedule, crofelemer is unable to reduce dacomitinib-induced diarrhoea, or maintain body weights. Ussing chamber data indicate that crofelemer is effectively inhibiting chloride secretion, yet this becomes redundant when co-treated with dacomitinib. Histopathological results are expected to reveal minimal damage (as hypothesized to be secretory diarrhoea).
Conclusion: Based on preliminary results it is hypothesized that crofelemer interacts with dacomitinib and is therefore not only ineffective at inhibiting associated diarrhoea, but in-fact exacerbates associated side effects. Results from this study may demonstrate that dacomitinib has a different mechanism of diarrhoea that traditional chemotherapy-induced diarrhoea indicated by chloride secretion experiments in ussing chambers and histological analysis.