Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA)

Regulatory Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: 150, P. 105640 - 105640

Published: May 14, 2024

N-Nitrosamine impurities, including nitrosamine drug substance-related impurities (NDSRIs), have challenged pharmaceutical industry and regulators alike affected the global supply over past 5 years. Nitrosamines are a class of known carcinogens, but NDSRIs posed additional challenges as many lack empirical data to establish acceptable intake (AI) limits. Read-across analysis from surrogates has been used identify AI limits in some cases; however, this approach is limited by availability robustly-tested matching structural features NDSRIs, which usually contain diverse array functional groups. Furthermore, absence surrogate resulted conservative cases, posing practical for impurity control. Therefore, new framework determining recommended was urgently needed. Here, Carcinogenic Potency Categorization Approach (CPCA) its supporting scientific rationale presented. The CPCA rapidly-applied structure-activity relationship-based method that assigns 1 categories, each with corresponding limit, reflecting predicted carcinogenic potency. considers number distribution α-hydrogens at N-nitroso center other activating deactivating affect α-hydroxylation metabolic activation pathway carcinogenesis. adopted internationally several regulatory authorities simplified starting point determine nitrosamines without need compound-specific data.

Language: Английский

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Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency

Chemical Research in Toxicology, Journal Year: 2024, Volume and Issue: 37(2), P. 181 - 198

Published: Feb. 5, 2024

A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate mutagenic potential and carcinogenic potency in rodents. Empirical computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at α-carbon; it responsible for both activation, leading formation DNA-reactive diazonium species, deactivation denitrosation. There are competing sites CYP metabolism (e.g., β-carbon), other reactive species can form following initial bioactivation, although these alternative tend decrease rather than enhance potency. The activation pathway, oxidative dealkylation, reaction drug carbonyl byproduct, e.g., formaldehyde, does not contribute toxic properties N-nitrosamines. Nitric oxide (NO), side product denitrosation, similarly be discounted as an enhancer toxicity based on carcinogenicity data substances act NO-donors. However, all N-nitrosamines potent rodent carcinogens. In significant number cases, there overlap with non-N-nitrosamine carcinogens Cohort Concern (CoC; high-potency comprising aflatoxin-like-, N-nitroso-, alkyl-azoxy compounds), while devoid potential. this context, mutagenicity useful surrogate carcinogenicity, proposed ICH M7 (R2) (2023) guidance. Thus, safety assessment control medicines, important those complementary attributes mechanisms structure–activity relationships translate elevated versus which associated reduction in, or absence of,

Language: Английский

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The Nitrosamine “Saga”: Lessons Learned from Five Years of Scrutiny

Organic Process Research & Development, Journal Year: 2023, Volume and Issue: 27(10), P. 1719 - 1735

Published: July 26, 2023

The onset of the N-nitrosamine (NA) saga in 2018 was chiefly related to certain small dialkyl N-nitrosamines originating from synthesis active pharmaceutical ingredient (API). However, subsequent comprehensive assessments performed on APIs, formulated drug products, and packaging put a different type NAs limelight: diverse range complex so-called nitrosamine drug-substance-related impurities (NDSRIs). They may form due presence potentially nitrosatable secondary or tertiary amine moieties APIs API nitrosating agents formed low levels nitrite present as impurities. unique properties functional group make it irreplaceable APIs. While be reduced, formation products cannot completely prevented, class default acceptable intake (AI) 18 ng/day currently poses significant challenges terms both viable control analysis at such levels. Even so, NA exposure through pharmaceuticals is expected orders magnitude lower than via food endogenous formation. robust carcinogenicity data are available for many small, simple NAs, there distinct absence most NDSRIs. Many working groups have therefore been established share rapidly improve knowledge (whether toxicity data, structure–activity relationships, analytical techniques), define best practices assess genotoxic potential NDSRIs, advance methods calculate AIs based solid scientific rationales. Ultimately, protect patients true cancer risk secure access important medicines, crucial manufacturers health authorities pursue efforts implement strategies that equally effective realistic. As patient safety paramount, industry committed ensuring medicines supplies safe effective. Where legitimate concerns exist, undisputed appropriate actions must taken, which could include withdrawal market.

Language: Английский

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Molecular similarity in chemical informatics and predictive toxicity modeling: from quantitative read-across (q-RA) to quantitative read-across structure–activity relationship (q-RASAR) with the application of machine learning

Critical Reviews in Toxicology, Journal Year: 2024, Volume and Issue: 54(9), P. 659 - 684

Published: Sept. 3, 2024

This article aims to provide a comprehensive critical, yet readable, review of general interest the chemistry community on molecular similarity as applied chemical informatics and predictive modeling with special focus read-across (RA) structure-activity relationships (RASAR). Molecular similarity-based computational tools, such quantitative (QSARs) RA, are routinely used fill data gaps for wide range properties including toxicity endpoints regulatory purposes. will explore background RA starting from how structural information has been through other contexts physicochemical, absorption, distribution, metabolism, elimination (ADME) properties, biological aspects being characterized. More recent developments RA's integration QSAR have resulted in emergence novel models ToxRead, generalized (GenRA), RASAR (q-RASAR). Conventional techniques excluded this except where necessary context.

Language: Английский

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Quantum Chemical Evaluation and QSAR Modeling of N-Nitrosamine Carcinogenicity

Chemical Research in Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

N-Nitrosamine compounds in pharmaceuticals are a major concern due to their carcinogenic potential. However, not all nitrosamines strong carcinogens, and understanding the structure-activity relationships of this compound group is challenge. The determination acceptable intake limits for determined by applying either simple potency categorization approach (CPCA) or read-across analysis from where experimental data exist. emergence structurally complex makes quantitative models desirable. Here, we present two-step modeling based on linear discriminant set quantum mechanical classical descriptors followed 3D-QSAR PLS regression model predict logTD50 nitrosamine compounds.

Language: Английский

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Acceptable intakes (AIs) for 11 small molecule N-nitrosamines (NAs)

Regulatory Toxicology and Pharmacology, Journal Year: 2023, Volume and Issue: 142, P. 105415 - 105415

Published: May 29, 2023

Low levels of N-nitrosamines (NAs) were detected in pharmaceuticals and, as a result, health authorities (HAs) have published acceptable intakes (AIs) to limit potential carcinogenic risk. The rationales behind the AIs not been provided understand process for selecting TD50 or read-across analog. In this manuscript we evaluated toxicity data eleven common NAs comprehensive and transparent consistent with ICH M7. This evaluation included substances which had datasets that robust, limited but sufficient, insufficient experimental animal carcinogenicity data. case robust sufficient information, calculated based on derived TD50s from most sensitive organ site. available structure activity relationships (SARs) applied categorical-based 1500 ng/day, 150 ng/day 18 ng/day; however additional (such biological computational modelling) could inform an alternative AI. approach advances methodology used derive NAs.

Language: Английский

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Estimation of acceptable daily intake values based on modeling and in vivo mutagenicity of NDSRIs of fluoxetine, duloxetine and atomoxetine

Regulatory Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: 152, P. 105672 - 105672

Published: July 4, 2024

Language: Английский

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Analytical Methodologies to Detect N-Nitrosamine Impurities in Active Pharmaceutical Ingredients, Drug Products and Other Matrices

Chemical Research in Toxicology, Journal Year: 2024, Volume and Issue: 37(9), P. 1456 - 1483

Published: Aug. 19, 2024

Since 2018, N-nitrosamine impurities have become a widespread concern in the global regulatory landscape of pharmaceutical products. This arises due to their potential for contamination, toxicity, carcinogenicity, and mutagenicity presence many active ingredients, drug products, other matrices. N-Nitrosamine humans can lead severe chemical toxicity effects. These include carcinogenic effects, metabolic disruptions, reproductive harm, liver diseases, obesity, DNA damage, cell death, chromosomal alterations, birth defects, pregnancy loss. They are particularly known cause cancer (tumors) various organs tissues such as liver, lungs, nasal cavity, esophagus, pancreas, stomach, urinary bladder, colon, kidneys, central nervous system. Additionally, may contribute development Alzheimer's Parkinson's diseases type-2 diabetes. Therefore, it is very important control or avoid them by enhancing effective analytical methodologies using cutting-edge techniques LC-MS, GC-MS, CE-MS, SFC, etc. Moreover, these methods need be sensitive selective with suitable precision accuracy, so that actual amounts detected quantified appropriately drugs. Regulatory agencies US FDA, EMA, ICH, WHO, focus more on hazards providing guidance regular updates manufacturers applicants. Similarly, should vigilant nitrosating agents secondary amines during manufacturing processes. Numerous review articles been published recently researchers, focusing found previously notified including sartans, metformin, ranitidine. also wide range Consequently, this aims concentrate products reported contain impurities. rifampicin, champix, famotidine, nizatidine, atorvastatin, bumetanide, itraconazole, diovan, enalapril, propranolol, lisinopril, duloxetine, rivaroxaban, pioglitazones, glifizones, cilostazol, sunitinib.

Language: Английский

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Re‐Evaluating Acceptable Intake: A Comparative Study of N‐Nitrosomorpholine and N‐Nitroso Reboxetine Potency

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: March 22, 2025

ABSTRACT Establishing regulatory limits for Drug Substance‐Related Impurities (NDSRIs) is challenging due to the limited genotoxicity and carcinogenicity data available many of these impurities, often leading conservative approaches. In this study, we evaluated genotoxic potential two structurally related nitrosamines: N‐nitrosomorpholine (NMOR) N‐nitroso reboxetine. Compared well‐studied NMOR, there little toxicological information Currently, both compounds have an acceptable intake value 127 ng/day, based on a read‐across using NMOR. While tested positive in series vitro vivo assays, found that mutagenic reboxetine was significantly lower than The benchmark dose (BMD) analysis mutagenicity supports 24,000 ng/day Computational studies, carried out quantum‐mechanical CADRE program, were consistent with outcomes, suggesting at or above 1500 comparison prediction supported by computed reactivity hydroxylation step, greater steric hindrance alpha carbons, more facile proton transfer heterolysis toward aldehyde metabolite. presented work can be used refine improve Carcinogenic Potency Categorization Approach (CPCA). It also underscores importance collaboration between authorities, pharmaceutical industry, scientific researchers address risks while avoiding overestimation certain NDSRIs.

Language: Английский

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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

Regulatory Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: 152, P. 105681 - 105681

Published: July 26, 2024

The finding of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in marketed drugs has led to implementation risk assessment processes intended limit exposures the entire class N-nitrosamines. A critical component process is establishing exposure limits that are protective human health. One approach for novel N-nitrosamines conduct an vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on provides decision making criteria based interpreting TGR studies as overall positive or negative. However, point departure metrics, such benchmark dose (BMD), can be used define potency provide opportunity establish relevant limits. This achieved through relative comparison with model possessing robust mutagenicity carcinogenicity data. current work adds dataset by providing data N-nitrosopiperidine (NPIP). In was also generated a N-nitrosamine impurity identified sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). Using approach, we have demonstrated safety NTTP at above levels 1500 ng/day.

Language: Английский

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