Drawing a Line: Where Might the Cohort of Concern End?

Ponting, David J.; Foster, R.

doi:10.1021/acs.oprd.3c00008

Cited by 14 publications

(9 citation statements)

References 83 publications

(185 reference statements)

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“…Kinetic modeling of the reaction demonstrated a good fit between experimentally observed NO-HCT 2 degradation kinetics and the derived model, where a reversible reaction step was predicted for transformation of 6 to 7 (see Supporting Information Pages S62–S64). This degradation pathway renders NO-HCT 2 as significantly less risky from a patient safety perspective as none of the species presented in Scheme are members of the cohort of concern mutagenic group …”

Section: Resultsmentioning

confidence: 99%

“…Sulfonyldiazonium species (R–SO 2 –N 2 + ) 7 was proposed as the key intermediate in the degradation of NO-HCT 2 , based on 1 H and 15 N NMR data, as well as formation of ABSA 3 as the key degradation product of 2 . Such species are analogous to sulfonic acid halides (R–SO 2 –X) and should therefore not be considered as a cohort of concern compound. At pH 1 to 5, different degradation pathways are also evidenced by the formation of HCT 1 and the diazonium salt 13 .…”

Section: Discussionmentioning

confidence: 99%

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Stability and Degradation Pathways of N-Nitroso-Hydrochlorothiazide and the Corresponding Aryl Diazonium Ion

Grahek¹,

Drev²,

Zupančič³

et al. 2023

Org. Process Res. Dev.

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Despite the fact that it was put on the market more than 60 years ago, hydrochlorothiazide (HCT) is still one of the most important antihypertensive drugs. Due to its chemical structure, which contains the secondary aryl-alkyl-amino moiety, it is vulnerable to the formation of N-nitrosamine drug substance-related impurity (NDSRI) N-nitroso-hydrochlorothiazide (NO-HCT). In our study, we reveal that NO-HCT degrades rapidly at pH values 6 to 8. The main degradation products identified are formaldehyde, thiatriazine, and aminobenzenesulfonic acid derivative. Interestingly, degradation of NO-HCT at pH values from 5 to 1 is significantly slower and provides a different impurity profile when compared to the profile generated between pH 6 and 8. Specifically, between pH 1 and 5, HCT is observed as one of the key degradation products of NO-HCT in addition to formaldehyde and aminobenzenesulfonic acid. Moreover, at pH 1, the aminobenzenesulfonic acid derivative is transformed to the corresponding diazonium salt in approximately 3% yield with the nitrosyl cation, which is released during the decomposition of NO-HCT to HCT. This diazonium is highly unstable above pH 5. To verify that degradation of NO-HCT does not produce the corresponding diazonium salt that could be formed via metabolic activation of NO-HCT, this diazonium salt and its hydrolytic and reduction degradation products were synthesized and used as standards for the identification of species formed during the degradation of NO-HCT. This enabled us to confirm that the corresponding aryl diazonium salt, which would be obtained from metabolic activation of NO-HCT, is not observed in the NO-HCT degradation pathway. Our study also demonstrates that this diazonium salt is stable only in the presence of a large excess of strong mineral acid under anhydrous conditions. In the presence of water, it is instantaneously converted to an aminobenzenesulfonic acid derivative. These findings suggest that the NO-HCT should not be considered as a typical compound belonging to the cohort of the concern.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Stability and Degradation Pathways of N-Nitroso-Hydrochlorothiazide and the Corresponding Aryl Diazonium Ion

Grahek¹,

Drev²,

Zupančič³

et al. 2023

Org. Process Res. Dev.

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“…In addition, the rate of DNA methylation correlated well with the rate of formaldehyde formation. Using 15 N-labeled NDMA as test material, Koepke et al 37 determined that, when incubated with isolated rat hepatocytes, 47% of the radiolabel was released as 15 N 2 . These results appear to show that less than 50% of NDMA is converted to methyldiazonium ion (7 in Figure 1) and that hydrolysis of the latter to methanol greatly reduces methylation of DNA bases to no more than 1% of the molar amount of added NDMA.…”

Section: ■ Methodsmentioning

confidence: 99%

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency

Snodin,

Trejo-Martin,

Ponting

et al. 2024

Chem. Res. Toxicol.

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

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“…Even NMPA, as the simplest aryl alkyl nitrosamine, could have been selected as a surrogate, although it would have been a very conservative selection because of the lack of steric hindrance (a methyl group at the α-position), low molecular weight, and no free carboxylate. Furthermore, nitrosamines with α-hydrogens but significant steric hindrance were recommended by Ponting and Foster to be potentially excluded from the CoC …”

Section: Defining a Commonly Accepted Strategy For Read-acrossmentioning

confidence: 99%

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

Nudelman

Kocks²,

Mouton

et al. 2023

Org. Process Res. Dev.

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

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Drawing a Line: Where Might the Cohort of Concern End?

Cited by 14 publications

References 83 publications

Stability and Degradation Pathways of N-Nitroso-Hydrochlorothiazide and the Corresponding Aryl Diazonium Ion

Stability and Degradation Pathways of N-Nitroso-Hydrochlorothiazide and the Corresponding Aryl Diazonium Ion

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency

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

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