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Utility of a next‐generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide

John Nicolette, Mirjam Luijten, Jennifer C. Sasaki, Laura Custer, Michelle Embry, Roland Froetschl, George Johnson Orcid Logo, Gladys Ouedraogo, Raja Settivari, Veronique Thybaud, Kerry L. Dearfield

Environmental and Molecular Mutagenesis, Volume: 62, Issue: 9, Pages: 512 - 525

Swansea University Author: George Johnson Orcid Logo

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DOI (Published version): 10.1002/em.22467

Abstract

We present a hypothetical case study to examine the use of a next-generation framework developed by the Genetic Toxicology Technical Committee of the Health and Environmental Sciences Institute for assessing the potential risk of genetic damage from a pharmaceutical perspective. We used etoposide, a...

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Published in: Environmental and Molecular Mutagenesis
ISSN: 0893-6692 1098-2280
Published: Wiley 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa58792
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We used etoposide, a genotoxic carcinogen, as a representative pharmaceutical for the purposes of this case study. Using the framework as guidance, we formulated a hypothetical scenario for the use of etoposide to illustrate the application of the framework to pharmaceuticals. We collected available data on etoposide considered relevant for assessment of genetic toxicity risk. From the data collected, we conducted a quantitative analysis to estimate margins of exposure (MOEs) to characterize the risk of genetic damage that could be used for decision-making regarding the predefined hypothetical use. We found the framework useful for guiding the selection of appropriate tests and selecting relevant endpoints that reflected the potential for genetic damage in patients. The risk characterization, presented as MOEs, allows decision makers to discern how much benefit is critical to balance any adverse effect(s) that may be induced by the pharmaceutical. Interestingly, pharmaceutical development already incorporates several aspects of the framework per regulations and health authority expectations. Moreover, we observed that quality dose response data can be obtained with carefully planned but routinely conducted genetic toxicity testing. 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spelling 2021-12-02T15:27:53.9726713 v2 58792 2021-11-25 Utility of a next‐generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2021-11-25 BMS We present a hypothetical case study to examine the use of a next-generation framework developed by the Genetic Toxicology Technical Committee of the Health and Environmental Sciences Institute for assessing the potential risk of genetic damage from a pharmaceutical perspective. We used etoposide, a genotoxic carcinogen, as a representative pharmaceutical for the purposes of this case study. Using the framework as guidance, we formulated a hypothetical scenario for the use of etoposide to illustrate the application of the framework to pharmaceuticals. We collected available data on etoposide considered relevant for assessment of genetic toxicity risk. From the data collected, we conducted a quantitative analysis to estimate margins of exposure (MOEs) to characterize the risk of genetic damage that could be used for decision-making regarding the predefined hypothetical use. We found the framework useful for guiding the selection of appropriate tests and selecting relevant endpoints that reflected the potential for genetic damage in patients. The risk characterization, presented as MOEs, allows decision makers to discern how much benefit is critical to balance any adverse effect(s) that may be induced by the pharmaceutical. Interestingly, pharmaceutical development already incorporates several aspects of the framework per regulations and health authority expectations. Moreover, we observed that quality dose response data can be obtained with carefully planned but routinely conducted genetic toxicity testing. This case study demonstrates the utility of the next-generation framework to quantitatively model human risk based on genetic damage, as applicable to pharmaceuticals. Journal Article Environmental and Molecular Mutagenesis 62 9 512 525 Wiley 0893-6692 1098-2280 etoposide; genetic toxicity; human health risk assessment; integrated testing strategy; mutagenicity 25 11 2021 2021-11-25 10.1002/em.22467 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2021-12-02T15:27:53.9726713 2021-11-25T14:55:03.8449589 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine John Nicolette 1 Mirjam Luijten 2 Jennifer C. Sasaki 3 Laura Custer 4 Michelle Embry 5 Roland Froetschl 6 George Johnson 0000-0001-5643-9942 7 Gladys Ouedraogo 8 Raja Settivari 9 Veronique Thybaud 10 Kerry L. Dearfield 11 58792__21773__e2ae197383e24254b0040ac8aaf1ce58.pdf 58792.pdf 2021-12-02T15:24:17.3413687 Output 2486433 application/pdf Version of Record true © 2021 The Authors. This is an open access article under the terms of the Creative Commons Attribution License true eng http://creativecommons.org/licenses/by/4.0/
title Utility of a next‐generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide
spellingShingle Utility of a next‐generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide
George Johnson
title_short Utility of a next‐generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide
title_full Utility of a next‐generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide
title_fullStr Utility of a next‐generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide
title_full_unstemmed Utility of a next‐generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide
title_sort Utility of a next‐generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide
author_id_str_mv 37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv 37d0f121db69fd09f364df89e4405e31_***_George Johnson
author George Johnson
author2 John Nicolette
Mirjam Luijten
Jennifer C. Sasaki
Laura Custer
Michelle Embry
Roland Froetschl
George Johnson
Gladys Ouedraogo
Raja Settivari
Veronique Thybaud
Kerry L. Dearfield
format Journal article
container_title Environmental and Molecular Mutagenesis
container_volume 62
container_issue 9
container_start_page 512
publishDate 2021
institution Swansea University
issn 0893-6692
1098-2280
doi_str_mv 10.1002/em.22467
publisher Wiley
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description We present a hypothetical case study to examine the use of a next-generation framework developed by the Genetic Toxicology Technical Committee of the Health and Environmental Sciences Institute for assessing the potential risk of genetic damage from a pharmaceutical perspective. We used etoposide, a genotoxic carcinogen, as a representative pharmaceutical for the purposes of this case study. Using the framework as guidance, we formulated a hypothetical scenario for the use of etoposide to illustrate the application of the framework to pharmaceuticals. We collected available data on etoposide considered relevant for assessment of genetic toxicity risk. From the data collected, we conducted a quantitative analysis to estimate margins of exposure (MOEs) to characterize the risk of genetic damage that could be used for decision-making regarding the predefined hypothetical use. We found the framework useful for guiding the selection of appropriate tests and selecting relevant endpoints that reflected the potential for genetic damage in patients. The risk characterization, presented as MOEs, allows decision makers to discern how much benefit is critical to balance any adverse effect(s) that may be induced by the pharmaceutical. Interestingly, pharmaceutical development already incorporates several aspects of the framework per regulations and health authority expectations. Moreover, we observed that quality dose response data can be obtained with carefully planned but routinely conducted genetic toxicity testing. This case study demonstrates the utility of the next-generation framework to quantitatively model human risk based on genetic damage, as applicable to pharmaceuticals.
published_date 2021-11-25T04:15:36Z
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