| アブストラクト | 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. |
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| ジャーナル名 | Toxicology |
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| Pubmed追加日 | 2025/12/2 |
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| 投稿者 | Tan, Shiyi; Yang, Yun; Ma, Li; Zuo, Xulei; Rao, Jianhua; Pu, Yuepu; Cheng, Feng; Gu, Zhongze; Zhang, Juan |
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| 組織名 | Key Laboratory of Environmental Medicine Engineering, Ministry of Education of;China, School of Public Health, Southeast University, Nanjing 210009, China.;Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical;University, Research Unit of Liver Transplantation and Transplant Immunology,;Chinese Academy of Medical Sciences, Nanjing 210000, China.;Chinese Academy of Medical Sciences, Nanjing 210000, China. Electronic address:;docchengfeng@nimu.edu.cn.;State Key Laboratory of Digital Medical Engineering, School of Biomedical;Engineering, Southeast University, Nanjing 211189, China; Jiangsu Institute for;Sports and Health (JISH), Nanjing 211100, China. Electronic address:;gu@seu.edu.cn.;China, School of Public Health, Southeast University, Nanjing 210009, China;;Jiangsu Institute for Sports and Health (JISH), Nanjing 211100, China. Electronic;address: zhangjuan@seu.edu.cn. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/41326256/ |
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