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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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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 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.
Keywords: N-Nitrosamines; Cohort of concern; Impurities; Carcinogenicity; Ames testing; In vivo mutation assay; Transgenic animals; Big Blue® rat; Benchmark dose modeling; Acceptable intake
College: Faculty of Medicine, Health and Life Sciences
Funders: Funding for this work was provided by Merck & Co., Inc.
Start Page: 105681

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