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N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP

Mark W. Powley, Zhanna Sobol, George Johnson Orcid Logo, Robert W. Clark, Stephen M. Dalby, Bridget A. Ykoruk, Alema Galijatovic-Idrizbegovic, Mark D. Mowery, Patricia A. Escobar

Regulatory Toxicology and Pharmacology, Volume: 152, Start page: 105681

Swansea University Author: George Johnson Orcid Logo

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DOI (Published version): 10.1016/j.yrtph.2024.105681

Abstract

The finding of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in marketed drugs has led to implementation of risk assessment processes intended to limit exposures to the entire class of N-nitrosamines. A critical component of the risk assessment process is establishing exposure limit...

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Published in: Regulatory Toxicology and Pharmacology
ISSN: 0273-2300
Published: Elsevier BV 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa67377
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A critical component of the risk assessment process is establishing exposure limits that are protective of human health. One approach to establishing exposure limits for novel N-nitrosamines is to conduct an in vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on N-nitrosamines provides decision making criteria based on interpreting in vivo TGR mutation studies as an overall positive or negative. However, point of departure metrics, such as benchmark dose (BMD), can be used to define potency and provide an opportunity to establish relevant exposure limits. This can be achieved through relative potency comparison of novel N-nitrosamines with model N-nitrosamines possessing robust in vivo mutagenicity and carcinogenicity data. The current work adds to the dataset of model N-nitrosamines by providing in vivo TGR mutation data for N-nitrosopiperidine (NPIP). In vivo TGR mutation data was also generated for a novel N-nitrosamine impurity identified in sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). 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spelling v2 67377 2024-08-14 N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 2024-08-14 MEDS The finding of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in marketed drugs has led to implementation of risk assessment processes intended to limit exposures to the entire class of N-nitrosamines. A critical component of the risk assessment process is establishing exposure limits that are protective of human health. One approach to establishing exposure limits for novel N-nitrosamines is to conduct an in vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on N-nitrosamines provides decision making criteria based on interpreting in vivo TGR mutation studies as an overall positive or negative. However, point of departure metrics, such as benchmark dose (BMD), can be used to define potency and provide an opportunity to establish relevant exposure limits. This can be achieved through relative potency comparison of novel N-nitrosamines with model N-nitrosamines possessing robust in vivo mutagenicity and carcinogenicity data. The current work adds to the dataset of model N-nitrosamines by providing in vivo TGR mutation data for N-nitrosopiperidine (NPIP). In vivo TGR mutation data was also generated for a novel N-nitrosamine impurity identified in sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). Using the relative potency comparison approach, we have demonstrated the safety of NTTP exposures at or above levels of 1500 ng/day. Journal Article Regulatory Toxicology and Pharmacology 152 105681 Elsevier BV 0273-2300 N-Nitrosamines; Cohort of concern; Impurities; Carcinogenicity; Ames testing; In vivo mutation assay; Transgenic animals; Big Blue® rat; Benchmark dose modeling; Acceptable intake 1 9 2024 2024-09-01 10.1016/j.yrtph.2024.105681 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee Funding for this work was provided by Merck & Co., Inc. 2024-09-20T16:19:09.4830535 2024-08-14T10:13:36.6135519 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Mark W. Powley 1 Zhanna Sobol 2 George Johnson 0000-0001-5643-9942 3 Robert W. Clark 4 Stephen M. Dalby 5 Bridget A. Ykoruk 6 Alema Galijatovic-Idrizbegovic 7 Mark D. Mowery 8 Patricia A. Escobar 9 67377__31425__ab3b8177736f47f18461003587747592.pdf 67377.VoR.pdf 2024-09-20T16:17:38.6887277 Output 844736 application/pdf Version of Record true © 2024 Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. and The Author(s). This is an open access article under the CC BY-NC-ND license. true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP
spellingShingle N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP
George Johnson
title_short N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP
title_full N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP
title_fullStr N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP
title_full_unstemmed N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP
title_sort N-nitrosamine impurity risk assessment in pharmaceuticals: Utilizing In vivo mutation relative potency comparison to establish an acceptable intake for NTTP
author_id_str_mv 37d0f121db69fd09f364df89e4405e31
author_id_fullname_str_mv 37d0f121db69fd09f364df89e4405e31_***_George Johnson
author George Johnson
author2 Mark W. Powley
Zhanna Sobol
George Johnson
Robert W. Clark
Stephen M. Dalby
Bridget A. Ykoruk
Alema Galijatovic-Idrizbegovic
Mark D. Mowery
Patricia A. Escobar
format Journal article
container_title Regulatory Toxicology and Pharmacology
container_volume 152
container_start_page 105681
publishDate 2024
institution Swansea University
issn 0273-2300
doi_str_mv 10.1016/j.yrtph.2024.105681
publisher Elsevier BV
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 - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description The finding of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in marketed drugs has led to implementation of risk assessment processes intended to limit exposures to the entire class of N-nitrosamines. A critical component of the risk assessment process is establishing exposure limits that are protective of human health. One approach to establishing exposure limits for novel N-nitrosamines is to conduct an in vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on N-nitrosamines provides decision making criteria based on interpreting in vivo TGR mutation studies as an overall positive or negative. However, point of departure metrics, such as benchmark dose (BMD), can be used to define potency and provide an opportunity to establish relevant exposure limits. This can be achieved through relative potency comparison of novel N-nitrosamines with model N-nitrosamines possessing robust in vivo mutagenicity and carcinogenicity data. The current work adds to the dataset of model N-nitrosamines by providing in vivo TGR mutation data for N-nitrosopiperidine (NPIP). In vivo TGR mutation data was also generated for a novel N-nitrosamine impurity identified in sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). Using the relative potency comparison approach, we have demonstrated the safety of NTTP exposures at or above levels of 1500 ng/day.
published_date 2024-09-01T16:19:07Z
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