Ceritinib-ibuprofen synergistic hepatotoxicity: Insights from real-world data and liver organoid models.

Ceritinib, a next-generation anaplastic lymphoma kinase inhibitor used to treat non-small cell lung cancer, has been increasingly associated with drug-induced liver injury (DILI), especially in the context of drug-drug interactions (DDIs). To elucidate the hepatotoxic risk of ceritinib in combination therapies, we conducted a real-world pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) and experimentally validated the results using human liver organoids. Disproportionality analysis revealed that ceritinib administered in combination therapy was more likely to induce DILI than its monotherapy, with the strongest correlation observed for ceritinib combined with ibuprofen (reporting odds ratio [ROR] = 12.01). Ibuprofen and acetaminophen (a classic DILI-associated drug with an ROR of 5.82) were selected for further combination studies using the liver organoid model. Both ceritinib-ibuprofen and ceritinib-acetaminophen combinations exhibited synergistic hepatotoxicity in organoids, with ceritinib-ibuprofen demonstrating a more pronounced effect, as demonstrated by the Bliss independence model based on organoid cell viability data. Mechanistically, ibuprofen possibly exacerbates ceritinib-induced hepatotoxicity by suppressing CYP3A4 activity, thereby impairing ceritinib metabolic clearance and enhancing its hepatotoxicity. Together, these findings provide a multidimensional understanding of DILI risks associated with ceritinib combination therapies. By integrating pharmacovigilance signals with physiologically relevant in vitro validation, this study highlights the utility of the human liver organoids for elucidating the mechanisms of hepatotoxicity insights and supporting safer prescribing practices, especially when ceritinib is co-administered with non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen in real-world clinical settings.