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Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal

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 F...

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Autores principales: Raschi, Emanuel, Fusaroli, Michele, Gatti, Milo, Caraceni, Paolo, Poluzzi, Elisabetta, De Ponti, Fabrizio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9146184/
https://www.ncbi.nlm.nih.gov/pubmed/35631471
http://dx.doi.org/10.3390/ph15050645
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author Raschi, Emanuel
Fusaroli, Michele
Gatti, Milo
Caraceni, Paolo
Poluzzi, Elisabetta
De Ponti, Fabrizio
author_facet Raschi, Emanuel
Fusaroli, Michele
Gatti, Milo
Caraceni, Paolo
Poluzzi, Elisabetta
De Ponti, Fabrizio
author_sort Raschi, Emanuel
collection PubMed
description 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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spelling pubmed-91461842022-05-29 Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal Raschi, Emanuel Fusaroli, Michele Gatti, Milo Caraceni, Paolo Poluzzi, Elisabetta De Ponti, Fabrizio Pharmaceuticals (Basel) Article 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. MDPI 2022-05-23 /pmc/articles/PMC9146184/ /pubmed/35631471 http://dx.doi.org/10.3390/ph15050645 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Raschi, Emanuel
Fusaroli, Michele
Gatti, Milo
Caraceni, Paolo
Poluzzi, Elisabetta
De Ponti, Fabrizio
Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal
title Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal
title_full Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal
title_fullStr Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal
title_full_unstemmed Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal
title_short Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal
title_sort liver injury with nintedanib: a pharmacovigilance–pharmacokinetic appraisal
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9146184/
https://www.ncbi.nlm.nih.gov/pubmed/35631471
http://dx.doi.org/10.3390/ph15050645
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