Use of less-than-lifetime (LTL) durational limits for nitrosamines: Case study of N-Nitrosodiethylamine (NDEA).

Autor: Bercu JP; Gilead Sciences, Nonclinical Safety and Pathobiology (NSP), Foster City, CA, USA. Electronic address: joel.bercu@gilead.com., Masuda-Herrera M; Gilead Sciences, Nonclinical Safety and Pathobiology (NSP), Foster City, CA, USA., Johnson G; Institute of Life Science, Swansea University Medical School, Singleton Park, Swansea, SA3 5DE, UK., Czich A; Sanofi, R&D Preclinical Safety, D-65926, Frankfurt, Germany., Glowienke S; Novartis AG, NIBR, Klybeckstrasse, CH-4057, Basel, Switzerland., Kenyon M; Pfizer Worldwide Research and Development, Genetic Toxicology, Eastern Point Road, Groton, CT, USA., Thomas R; Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK., Ponting DJ; Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK., White A; GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG12 0DP, UK., Cross K; Leadscope Inc. an Instem Company, Columbus, OH, 43215, USA., Waechter F; Aché Laboratórios Farmacêuticos S.A., Rodovia Presidente Dutra, km 222,2, Porto da Igreja, 07034-904, Guarulhos, SP, Brazil., Rodrigues MAC; Brazilian Health Regulatory Agency, ANVISA, Brasilia, Brazil.
Jazyk: angličtina
Zdroj: Regulatory toxicology and pharmacology : RTP [Regul Toxicol Pharmacol] 2021 Jul; Vol. 123, pp. 104926. Date of Electronic Publication: 2021 Apr 13.
DOI: 10.1016/j.yrtph.2021.104926
Abstrakt: The ICH M7(R1) guideline describes a framework to assess the carcinogenic risk of mutagenic and carcinogenic pharmaceutical impurities following less-than-lifetime (LTL) exposures. This LTL framework is important as many pharmaceuticals are not administered for a patient's lifetime and as clinical trials typically involve LTL exposures. While there has been regulatory caution about applying LTL concepts to cohort of concern (COC) impurities such as N-nitrosamines, ICH M7 does not preclude this and indeed literature data suggests that the LTL framework will be protective of patient safety for N-nitrosamines. The goal was to investigate if applying the LTL framework in ICH M7 would control exposure to an acceptable excess cancer risk in humans. Using N-nitrosodiethylamine as a case study, empirical data correlating exposure duration (as a percentage of lifespan) and cancer incidence in rodent bioassays indicate that the LTL acceptable intake (AI) as derived using the ICH M7 framework would not exceed a negligible additional risk of cancer. Therefore, controlling N-nitrosamines to an LTL AI based on the ICH M7 framework is thus demonstrated to be protective for potential carcinogenic risk to patients over the exposure durations typical of clinical trials and many prescribed medicines.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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