| アブストラクト | Drug-induced liver injury (DILI) with nintedanib has emerged as an adverse event of special interest in premarketing clinical trials. We characterized DILI with nintedanib in the real world and explored the underlying pharmacological basis. First, we assessed serious hepatic events reported to the Food and Drug Administration's Adverse Event Reporting System by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Demographic and clinical features were inspected (seriousness, onset, discontinuation, dechallenge/rechallenge, concomitant drugs) to implement an ad hoc causality assessment scoring system. Second, we appraised physiochemical and pharmacokinetic parameters possibly predictive of DILI occurrence. Significant disproportionality was found for nintedanib as compared to pirfenidone (N = 91; ROR = 4.77; 95% CI = 3.15-7.39). Asian population, low body weight (59 kg), and rapid DILI onset (13.5 days) emerged as clinical features. Hospitalization and discontinuation were found in a significant proportion of cases (32% and 36%, respectively). In 24% of the cases, at least two potentially hepatotoxic drugs (statins, proton pump inhibitors, antibiotics) were recorded. Causality was at least possible in 92.3% of the cases. High lipophilicity and predicted in silico inhibition of liver transporters emerged as potential pharmacokinetic features supporting the biological plausibility. Although causality cannot be demonstrated, clinicians should consider early monitoring and medication review on a case-by-case basis. |
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| ジャーナル名 | Pharmaceuticals (Basel, Switzerland) |
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| 投稿日 | 2022/5/29 |
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| 投稿者 | Raschi, Emanuel; Fusaroli, Michele; Gatti, Milo; Caraceni, Paolo; Poluzzi, Elisabetta; De Ponti, Fabrizio |
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| 組織名 | Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater;Studiorum University of Bologna, 40126 Bologna, Italy.;Department of Medical and Surgical Sciences, Alma Mater Studiorum University of;Bologna, 40138 Bologna, Italy.;SSD Clinical Pharmacology, Department for Integrated Infectious Risk Management,;IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy.;IRCCS AOU di Bologna-Policlinico di S. Orsola, 40138 Bologna, Italy.;Center for Biomedical Applied Research, Alma Mater Studiorum University of;Bologna, 40126 Bologna, Italy. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/35631471/ |
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