Using SAFEPATH to Uncover a Novel Mechanism of Hepatotoxicity for Gefitinib

This white paper details the research conducted by Ignota Labs using their advanced causal and explainable AI technology, SAFEPATH, to analyse the mechanisms of hepatotoxicity for two EGFR-TKI inhibitors, Erlotinib and Gefitinib, the latter having an as yet unknown mechanism of toxicity. The known mechanism of UGT1A1-mediated toxicity of Erlotinib was recovered, and a novel sphingolipid metabolism mechansim of toxicity of Gefitinib was hypothesised and subsequently experimentally validated. Crucially, we were also able to suggest the reason for the observed heterogeneous toxicity response to Gefitinib. This study exemplifies the potential of integrating AI tools with comprehensive datasets to improve drug safety and patient management.