Abstract
Background
Idiosyncratic drug reactions such as hepatotoxicity and blood dyscrasias represent one of the major causes of drug withdrawal from the market. According to the reactive metabolite (RM) concept, this may be due to the metabolic activation of structural alerts (SAs), functionalities in the drug molecule that are susceptible to bioactivation resulting in RMs. The relationship, however, between metabolic activation of SAs in drugs with in vivo toxicity measured as disproportionate reporting of adverse drug reactions (ADRs) to the WHO VigiBase™ database has never been studied.
Objective
The objective of this study was to investigate whether reported associations of hepatotoxicity between NSAIDs with SAs and NSAIDs with mitigated SAs are disproportionately present in the ADR reporting VigiBase™ database of the WHO collaborating center (the Uppsala Monitoring Centre). The extent of disproportionality of these associations is compared with associations of NSAIDs and hemorrhage, an ADR not associated with the forming of RMs.
Methods
We calculated the reporting odds ratios for five NSAIDs [bromfenac (withdrawn), lumiracoxib (withdrawn), diclofenac, ibuprofen, and naproxen] associated with the MedDRA preferred terms: hepatic failure, hepatic function abnormal, hepatic necrosis, and hepatitis. The disproportionality of the association of these ADRs is compared with the preferred term hemorrhage.
Results
The results show that hepatotoxicity is more disproportionately reported in the WHO database for NSAIDs with SAs (bromfenac, lumiracoxib, diclofenac) than for NSAIDs where SAs are mitigated (ibuprofen and naproxen). This difference in reporting between NSAIDs with SAs and with mitigated SAs is not observed for the ADR hemorrhage, an ADR not associated with the forming of RMs.
Conclusions
This study shows that although spontaneous reports have many limitations, the findings are in line with previous research on the reactive metabolite concept. Whether SAs and the number of SAs in the NSAIDs actually play a role in the observed hepatotoxicity must be investigated in future studies.
Notes
MedDRA® terminology is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). MedDRA® trademark is owned by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) on behalf of ICH.
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Disclosures
The authors are indebted to the national pharmacovigilance centers that contributed data to the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (WHO-UMC), and therefore to this study. The opinions and conclusions, however, are not necessarily those of the various centers, nor of the WHO-UMC. The information originates from a variety of sources, and the likelihood that the suspected adverse reaction is drug related is not the same in all cases. For a statement regarding data released from the UMC, the WHO Collaborating Centre for International Drug Monitoring, please visit http://www.who-umc.org/graphics/25300.pdf.
Funding and conflict of interest
No sources of funding were used to assist in the preparation of this study. Naomi Jessurun and Eugène van Puijenbroek have no conflicts of interest that are directly relevant to the content of this study.
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Jessurun, N., van Puijenbroek, E. Relationship Between Structural Alerts in NSAIDs and Idiosyncratic Hepatotoxicity: An Analysis of Spontaneous Report Data from the WHO Database. Drug Saf 38, 511–515 (2015). https://doi.org/10.1007/s40264-015-0282-z
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DOI: https://doi.org/10.1007/s40264-015-0282-z