Current Threat of Nitrosamines in Pharmaceuticals and Scientific Strategies for Risk Mitigation

Journal of Pharmaceutical Sciences, Год журнала: 2023, Номер 112(5), С. 1192 - 1209

Опубликована: Фев. 4, 2023

Язык: Английский

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

Environmental and Molecular Mutagenesis, Год журнала: 2025, Номер unknown

Опубликована: Март 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.

Язык: Английский

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Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(23), С. 15584 - 15607

Опубликована: Ноя. 28, 2022

The detection of N-nitrosamines, derived from solvents and reagents and, on occasion, the active pharmaceutical ingredient (API) at higher than acceptable levels in drug products, has led regulators to request a detailed review for their presence all medicinal products. In absence rodent carcinogenicity data novel N-nitrosamines amine-containing APIs, conservative class limit 18 ng/day (based most carcinogenic N-nitrosamines) or derivation intakes (AIs) using structurally related surrogates with robust is recommended. guidance implications industry given vast number marketed drugs. this perspective, rate-limiting step N-nitrosamine carcinogenicity, involving cytochrome P450-mediated α-carbon hydroxylation yield DNA-reactive diazonium carbonium ion intermediates, discussed reference selection read-across analogs derive AIs. Risk-mitigation strategies managing putative preclinical discovery setting are also presented.

Язык: Английский

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Revisiting the Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals

Journal of Pharmaceutical Sciences, Год журнала: 2023, Номер 112(12), С. 3005 - 3011

Опубликована: Окт. 5, 2023

Abstract

N-Nitrosamines are a class of indirect acting mutagens, as their metabolic degradation leads to the formation DNA-alkylating diazonium ion. Following up on in-silico identification thousands nitrosamines that can potentially be derived from small molecule drugs and known impurities described in previous publication, we have now re-analyzed this dataset apply EMA's Carcinogenic Potency Categorization Approach (CPCA) introduced with 16^th revision Q&A document for Marketing Authorization Holders. We find majority potential secondary amine precursors belongs potency categories 4 5, corresponding an acceptable daily intake 1500 ng, whereas tertiary distribute more evenly among all categories, resulting substantial number structures assigned challenging intakes 18 ng/day 100 1 2, respectively. However, nitrosative dealkylation pathway is generally far slower than direct nitrosation amines, mechanism suspected only featuring electron-rich (hetero)aromatic substituents. This allows greater focus towards those require further review, demonstrate not substantial. In addition, reflect nitrosamine risk posed by API based ICH Q3A/B threshold unknown may exist could transformed relevant amounts NA. also analytical sensitivity required quantification high problematic especially dose APIs. summary, regulatory framework rolled out latest represents improvement compared situation, but refinement through interaction between manufacturers, regulators, not-for-profit academic institutions will ensure patient access vital medicines without compromising safety.

Язык: Английский

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Approaches and Considerations for the Investigation and Synthesis of N-Nitrosamine Drug Substance-Related Impurities (NDSRIs)

Organic Process Research & Development, Год журнала: 2023, Номер 27(10), С. 1784 - 1791

Опубликована: Май 30, 2023

N-Nitrosamine risk assessment of pharmaceuticals has moved from an initial focus on the potential presence known small-molecule N-nitrosamines such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in active substances toward for generation more complex nitrosamine drug substance-related impurities (NDSRIs) products. While N-nitrosation simple secondary amines is well-understood, can undergo alternative reaction pathways that be challenging to predict. A number are not but either unreactive or react by C-nitrosation nitration generate non-N-nitrosamine This article proposes a standard set three orthogonal nitrosation forced degradation type conditions used investigate novel amines. These complementary considered provide thorough evaluation N-nitrosamine formation with respect factors within pharmaceutical manufacturing. If, after investigation under proposed conditions, isolation possible, resultant understanding chemical reactivity stability justify question would expected generated amine substance product. If formed these information gained part also provides starting point development process synthesize discrete sample further testing. Additionally, synthetic analytical considerations should taken into account during preparation use toxicological studies discussed.

Язык: 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, Год журнала: 2024, Номер 152, С. 105681 - 105681

Опубликована: Июль 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.

Язык: Английский

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Making the Case for Quantum Mechanics in Predictive Toxicology─Nearly 100 Years Too Late?

Chemical Research in Toxicology, Год журнала: 2023, Номер 36(9), С. 1444 - 1450

Опубликована: Сен. 7, 2023

The use of quantum mechanics (QM) has long been the norm to study covalent-binding phenomena in chemistry and biochemistry. pharmaceutical industry leverages QM models explicitly covalent drug discovery implicitly characterize short-range interactions noncovalent binding. Predictive toxicology resisted widespread adoption QM, including industry, despite its obvious relevance metabolic processes upstream adverse outcome pathways advances both methods computational resources, which support fit-for-purpose applications reasonable timeframes. Here, we make case for embracing as an indispensable part a toxicologist's toolkit. We argue that provides necessary orthogonality alert-based expert systems traditional QSARs, consistent with calls animal-free integrated testing strategies safety assessments commercial chemicals. outline existing roadblocks this transition, need train model developers shift toward service-based toxicity utilize high-performance computing clusters. Lastly, describe recent examples successful implementations hazard propose how silico can be further advanced by integrating artificial intelligence.

Язык: Английский

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The comprehensive prediction of carcinogenic potency and tumorigenic dose (TD50) for two problematic N-nitrosamines in food: NMAMPA and NMAMBA using toxicology in silico methods

Chemico-Biological Interactions, Год журнала: 2024, Номер 389, С. 110864 - 110864

Опубликована: Янв. 8, 2024

Язык: Английский

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Quantum Mechanical Assessment of Nitrosamine Potency

Chemical Research in Toxicology, Год журнала: 2024, Номер 37(6), С. 1011 - 1022

Опубликована: Май 28, 2024

Nitrosamines are in the cohort of concern (CoC) as determined by regulatory guidance. CoC compounds considered highly potent carcinogens that need to be limited below threshold toxicological concern, 1.5 μg/day. like NDMA and NDEA require strict control, while novel nitrosamine drug substance-related impurities (NDSRIs) may or not characterized carcinogens. A risk assessment based on structural features NDSRIs is important order predict potency because they lack substance-specific carcinogenicity. Herein, we present a quantum mechanical (QM)-based analysis structurally diverse sets nitrosamines better understand how structure influences reactivity could result We describe trend through activation energies corresponding α-hydroxylation, aldehyde formation, diazonium intermediate reaction with DNA base, hydrolysis reactions, other probable metabolic pathways associated carcinogenicity nitrosamines. evaluated for selected cases such N-nitroso pyrrolidines, piperidines, piperazines, morpholines, thiomorpholine, N-methyl nitroso aromatic, fluorine-substituted nitrosamines, substituted aliphatic compare these results recent framework carcinogenic characterization approach (CPCA) proposed health authorities which meant give guidance acceptable intakes (AI) lacking data. show examples where QM modeling CPCA aligned both underestimates overestimates AI. In predicts high NDSRIs, can help estimate an Our suggest combined mechanistic understanding hydrolysis, bases identify underpin anticipate this work will valuable addition provide more analytical way AI NDSRIs.

Язык: Английский

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Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage

Regulatory Toxicology and Pharmacology, Год журнала: 2023, Номер 145, С. 105505 - 105505

Опубликована: Окт. 5, 2023

N-nitrosamines (NAs) are a class of compounds which many, especially the small dialkyl type, indirect acting DNA alkylating mutagens. Their presence in pharmaceuticals is subject to very strict acceptable daily intake (AI) limits, traditionally expressed on mass basis. Here we demonstrate that AIs not experimentally derived for specific compound, but via statistical extrapolation or read across suitable analog, should be molar scale corrected target substance's molecular weight. This would account mechanistic aspect each nitroso group can, at maximum, single mutation and number molecules per unit proportional weight (MW). In this regard have re-calculated EMA 18 ng/day regulatory default AI unknown nitrosamines propose revised 163 pmol/day. addition, provide MW-corrected those nitrosamine drug substance related impurities (NDSRIs) has pre-assigned by read-across. Regulatory acceptance fundamental scientific tenet allow one derive limits NDSRIs both meet health-protection goals technically feasible.

Язык: Английский

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