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The Use of Subgroup Disproportionality Analyses to Explore the Sensitivity of a Global Database of Individual Case Safety Reports to Known Pharmacogenomic Risk Variants Common in Japan

INTRODUCTION: Genetic variations of enzymes that affect the pharmacokinetics and hence effects of medications differ between ethnicities, resulting in variation in the risk of adverse drug reactions (ADR) between different populations. Previous work has demonstrated that risk-group considerations ca...

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Autores principales: Wakao, Rika, Lönnstedt, Ingrid M., Aoki, Yasunori, Chandler, Rebecca E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184560/
https://www.ncbi.nlm.nih.gov/pubmed/33837924
http://dx.doi.org/10.1007/s40264-021-01063-1
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author Wakao, Rika
Lönnstedt, Ingrid M.
Aoki, Yasunori
Chandler, Rebecca E.
author_facet Wakao, Rika
Lönnstedt, Ingrid M.
Aoki, Yasunori
Chandler, Rebecca E.
author_sort Wakao, Rika
collection PubMed
description INTRODUCTION: Genetic variations of enzymes that affect the pharmacokinetics and hence effects of medications differ between ethnicities, resulting in variation in the risk of adverse drug reactions (ADR) between different populations. Previous work has demonstrated that risk-group considerations can be incorporated into approaches of statistical signal detection. It is unknown whether databases of individual case safety reports (ICSRs) are sensitive to pharmacogenomic differences between populations. OBJECTIVE: The aim of this study was to explore the sensitivity of a global database of ICSRs to known pharmacogenomic risk variants common in Japan. METHODS: The data source was VigiBase, the global database of ICSRs, including all reports entered in the version frozen on 5 January 2020. Subgroup disproportionality analysis was used to compare ICSRs of two subgroups, Japan and rest of world (RoW). Reports for UGT1A1-metabolized irinotecan and the CYP2C19-metabolized drugs voriconazole, escitalopram and clopidogrel were selected for comparison between the subgroups based upon known genetic polymorphisms with high prevalence in Japan. Contrast between the subgroups was quantified by IC delta [Formula: see text] ), a robust shrinkage observed-to-expected (OE) ratio on a log scale. Harmonic mean p values (HMP) were calculated for each drug to evaluate whether a list of pre-specified ADRs were collectively significantly over- (or under-)reported as hypothesized. Daily drug dosages were calculated for ICSRs with sufficient information, and dose distributions were compared between Japan and RoW and related to differences in regionally approved doses. RESULTS: The predictions of over-reporting patterns for specific ADRs were observed and confirmed in bootstrap HMP analyses (p = 0.004 for irinotecan and p < 0.001 for each of voriconazole, escitalopram and clopidogrel) and compared with similar drugs with different metabolic pathways. The impact of proactive regulatory action, such as recommended dosing and therapeutic drug monitoring (TDM), was also observable within the global database. For irinotecan and escitalopram, there was evidence of use of lower dosages as recommended in the Japanese labels; for voriconazole, there was evidence of use of TDM with an over-reporting of terms related to drug level measurements and an under-reporting of liver toxicity. CONCLUSIONS: Pharmaco-ethnic vulnerabilities caused by pharmacogenomic differences between populations may contribute to differences in ADR reporting between countries in a global database of ICSRs. Regional analyses within a global database can inform on the effectiveness of local risk minimization measures and should be leveraged to catalyse the conversion of real-world usage into safer use of drugs in ethnically tailored ways. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40264-021-01063-1.
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spelling pubmed-81845602021-06-25 The Use of Subgroup Disproportionality Analyses to Explore the Sensitivity of a Global Database of Individual Case Safety Reports to Known Pharmacogenomic Risk Variants Common in Japan Wakao, Rika Lönnstedt, Ingrid M. Aoki, Yasunori Chandler, Rebecca E. Drug Saf Original Research Article INTRODUCTION: Genetic variations of enzymes that affect the pharmacokinetics and hence effects of medications differ between ethnicities, resulting in variation in the risk of adverse drug reactions (ADR) between different populations. Previous work has demonstrated that risk-group considerations can be incorporated into approaches of statistical signal detection. It is unknown whether databases of individual case safety reports (ICSRs) are sensitive to pharmacogenomic differences between populations. OBJECTIVE: The aim of this study was to explore the sensitivity of a global database of ICSRs to known pharmacogenomic risk variants common in Japan. METHODS: The data source was VigiBase, the global database of ICSRs, including all reports entered in the version frozen on 5 January 2020. Subgroup disproportionality analysis was used to compare ICSRs of two subgroups, Japan and rest of world (RoW). Reports for UGT1A1-metabolized irinotecan and the CYP2C19-metabolized drugs voriconazole, escitalopram and clopidogrel were selected for comparison between the subgroups based upon known genetic polymorphisms with high prevalence in Japan. Contrast between the subgroups was quantified by IC delta [Formula: see text] ), a robust shrinkage observed-to-expected (OE) ratio on a log scale. Harmonic mean p values (HMP) were calculated for each drug to evaluate whether a list of pre-specified ADRs were collectively significantly over- (or under-)reported as hypothesized. Daily drug dosages were calculated for ICSRs with sufficient information, and dose distributions were compared between Japan and RoW and related to differences in regionally approved doses. RESULTS: The predictions of over-reporting patterns for specific ADRs were observed and confirmed in bootstrap HMP analyses (p = 0.004 for irinotecan and p < 0.001 for each of voriconazole, escitalopram and clopidogrel) and compared with similar drugs with different metabolic pathways. The impact of proactive regulatory action, such as recommended dosing and therapeutic drug monitoring (TDM), was also observable within the global database. For irinotecan and escitalopram, there was evidence of use of lower dosages as recommended in the Japanese labels; for voriconazole, there was evidence of use of TDM with an over-reporting of terms related to drug level measurements and an under-reporting of liver toxicity. CONCLUSIONS: Pharmaco-ethnic vulnerabilities caused by pharmacogenomic differences between populations may contribute to differences in ADR reporting between countries in a global database of ICSRs. Regional analyses within a global database can inform on the effectiveness of local risk minimization measures and should be leveraged to catalyse the conversion of real-world usage into safer use of drugs in ethnically tailored ways. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40264-021-01063-1. Springer International Publishing 2021-04-10 2021 /pmc/articles/PMC8184560/ /pubmed/33837924 http://dx.doi.org/10.1007/s40264-021-01063-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original Research Article
Wakao, Rika
Lönnstedt, Ingrid M.
Aoki, Yasunori
Chandler, Rebecca E.
The Use of Subgroup Disproportionality Analyses to Explore the Sensitivity of a Global Database of Individual Case Safety Reports to Known Pharmacogenomic Risk Variants Common in Japan
title The Use of Subgroup Disproportionality Analyses to Explore the Sensitivity of a Global Database of Individual Case Safety Reports to Known Pharmacogenomic Risk Variants Common in Japan
title_full The Use of Subgroup Disproportionality Analyses to Explore the Sensitivity of a Global Database of Individual Case Safety Reports to Known Pharmacogenomic Risk Variants Common in Japan
title_fullStr The Use of Subgroup Disproportionality Analyses to Explore the Sensitivity of a Global Database of Individual Case Safety Reports to Known Pharmacogenomic Risk Variants Common in Japan
title_full_unstemmed The Use of Subgroup Disproportionality Analyses to Explore the Sensitivity of a Global Database of Individual Case Safety Reports to Known Pharmacogenomic Risk Variants Common in Japan
title_short The Use of Subgroup Disproportionality Analyses to Explore the Sensitivity of a Global Database of Individual Case Safety Reports to Known Pharmacogenomic Risk Variants Common in Japan
title_sort use of subgroup disproportionality analyses to explore the sensitivity of a global database of individual case safety reports to known pharmacogenomic risk variants common in japan
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184560/
https://www.ncbi.nlm.nih.gov/pubmed/33837924
http://dx.doi.org/10.1007/s40264-021-01063-1
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