Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer

Area of Science:

• Oncology
• Pharmacology
• Gastroenterology

Background:

• Dacomitinib, a pan-ErbB tyrosine kinase inhibitor (TKI), frequently causes diarrhea, potentially via chloride secretion.
• Crofelemer, an antisecretory agent, was investigated as a potential intervention for dacomitinib-induced diarrhea.

Purpose of the Study:

• To evaluate the efficacy of crofelemer in mitigating dacomitinib-induced diarrhea and gastrointestinal dysfunction.
• To investigate the underlying mechanisms of dacomitinib-induced diarrhea and the effect of crofelemer on these processes.

Main Methods:

• Electrogenic ion analysis using T84 cell monolayers in Ussing chambers.
• In vivo study in Albino Wistar rats treated with dacomitinib and/or crofelemer.
• Assessment of intestinal barrier function, tight junction protein integrity, and histopathology.

Main Results:

• Crofelemer attenuated dacomitinib-induced chloride secretion in vitro but significantly worsened diarrhea and weight loss in vivo.
• Crofelemer lost its anti-secretory action in the presence of dacomitinib in rats.
• Dacomitinib induced proteolysis of tight junction proteins (ZO-1, occludin) and barrier dysfunction, which crofelemer did not ameliorate.

Conclusions:

• Crofelemer exacerbated dacomitinib-induced diarrhea in a preclinical model.
• Antisecretory drug therapy may be ineffective or even detrimental for managing dacomitinib-induced diarrhea.
• Further research is needed to understand and manage TKI-induced gastrointestinal toxicities.