Valsartan & Hydrochlorothiazide related NDSRIs

Dear Experts,
Need your help.
Anybody does idea about Valsartan & Hydrochlorothiazide related NDSRIs.
such as
N-Nitroso Valsartan Methyl ester Impurity
image
N-Nitroso Valsartan
image
Hydrochlorothiazide Nitroso Impurity-1
image
N-Nitroso Hydrochlorothiazide EP Impurity C
image

Need help for AI as per read across.

@Sarada.jena Can you share a bit more information on the findings of your team related to this inquiry? Perhaps sharing your preliminary assessment…

Hi,

EMA has mentioned some information in this document for example:
Lessons learnt from presence of N-nitrosamine impurities in sartan medicines

2.3.1. The sartans case
Formation of N-nitrosamines in sartans
‚ÄúDuring the Article 31 review of sartans, two valsartan-related N-nitrosamine impurities were identified. One was found not to be mutagenic following Ames testing. No data was provided for the second structurally related impurity, although the MAH argued that the structural similarity was sufficient to consider it non-mutagenic. The assessors considered that the second impurity was likely to have significantly different physicochemical properties and in vivo behaviour. Therefore, Ames testing was requested. Data from Ames testing was subsequently submitted and deemed by EDQM to adequately demonstrate non-mutagenicity of the second impurity. This demonstrates that some compounds containing N-nitrosamine functionality may not be mutagenic.‚ÄĚ

Hello,

As rightly cited by pagelm, for valsartan related nitrosamine impurities you may consider the EMA article since both these impurities have been accepted as non-mutagenic based on the negative Ames results. However, I am not sure if the regulatory authorities will accept the same argument in the current times because the Ames test itself has some limitations towards mutagenicity of N-nitrosamines (unless performed using Hamster liver homogenase) and follow-up in vivo TGR (Mutamouse) study.

Regarding N-Nitroso Hydrochlorothiazide EP Impurity C, you may relook if this is really a cohort of concern compound since it is not a ‚Äúdialkyl N-nitrosamine‚ÄĚ.

image
It seems to me that this structure should rather be considered as the nitroso derivative of hydrochlorothiazide impurity C.
Regarding nitroso HCTZ itself, it is a substance known for a long time and its toxicity has been the subject of research.
I do not know how reliable this data is, but it seems to me that it may be the starting point for establishing AI.

1 Like