Nitrosamine will be generated in our body, even though it is not included in drug products. 1 mM nitrite caused an increase above the acceptable daily intake set by the U.S. Food and Drug Administration (FDA) for some of the metformin drugs.
According to the article, one pound of cured meat could bring 5mM nitrite.
https://www.nature.com/articles/s41598-024-63032-9
I guess the amounts of DMA in the tablets may be different.
1 mM nitrite is high, I don’t know if we have to use 96 ng/day here and if the model shouldn’t be finetuned to intake together with a meal (not just keeping cured meat-like nitrite exposure, but also antioxidants and amine scavengers).
It disturbs me a little bit that the point of departure is 96 ng NDMA/day as acceptable exposure without nuancing. The RAIL for exogenous contamination in medicines is not per se the basis for evaluation of endogenous formation. When we start to go endogenously I think this is moving away from unintegrated exposure scenarios and looking more holistically, with reduced possibility to distinct on the origin of NDMA and also looking at combinations of factors (e.g. nitrite from food) and faith, leading to more advanced exposure models for balancing risks.
The nitrite in the stomach is obviously not going to come from the medicine and nitrite preservative use is maybe a little bit too widespread to add this as meal restriction on the leaflet, so assessment of the risks merges the food and medicine perspective. If you want to look at this from a regulatory toxicology perspective (which is done by citing only pharma-regulation linked AI for NDMA), food and pharma have to agree first on the acceptable exposure to NDMA? This is not the case today, see for example:
In pharma we are often used to looking at exposure unintegrated, also for multi- (endo, exo or end/exo) root cause impurities (typically ignoring biokinetics and other sources of risks), but typically pay the price for this limitation with conservative limits/extra precaution. As endogenous nitrosamine formation is not new in literature, also not linked to API, possibly the conservative RAIL for medicines (for NDMA, CPCA,…) can be interpreted in this precautionary sense. Increasing quantification of endogenous risk to in the future allow to couple back to exogenous limits and thus more holistic models is thus useful.
It would have been useful not only to compare with the exogenous NDMA limits for pharma, but also with NDMA endogenous formation baseline levels and NDMA exposure from foods which can be in totality much higher than 96 ng/day.
I found it strange that the fact that metformin has to be taken with meals is seen per definition as increased risk (or as subscribing the relevance of the study conditions used), as this would require establishing that the average meal is more contributing to nitrite risks than to antioxidant-linked or alternative amine-scavenger derisking (e.g. N-terminal proline) for the scenario? Especially because the tests are done in vitro with simulated gastric fluid without varying parameters like spiking with proline or ascorbic acid (see for example), but while using high nitrite concentrations (simulating only the worst case elements of a meal). Even the exposure to nitrites as preservatives in cured meat goes hand in hand with the dosing of N-terminal proline or other biogenic amines, whereas also this type of preservative use has become increasingly regulated (quite recently updated in Europe in fact). Nitrosamines risks for high nitrite high amine foods is a study field on its own.
For stomach nitrites, the “closest concentration to physiologic conditions used, 1 mM” seems quite high (or (cured meat) meal-like)?
0.100 L volume gastric fluid (fasting…) x 1/1000 M nitrites (non-fasting…) = 0.0001 mol x 46 g/mol = 4.6 mg <=> The ADI of nitrites is 0.07 mg/kg bw
/ 150 mg nitrites/kg food (max. nitrite preservative use in Europe) = 31 g of high nitrite food product
On stomach nitrite concentration see also review in link. 1 mM is really a high nitrite concentration. So considering max. 400 ng NDMA/tablet for the tested conditions (I guess 1-2 tablets/day) (and the discussions on applicable acceptable exposure for NDMA and real exposure) with a possibility to optimize further for the meal scenario, the data might as well contribute to derisking in the end. So fully support more work is indeed required.
What do we think was the rationale behind selecting pH 2.5? (Empty stomach is pH 1.5, pH 3.15 usually selected for maximum conversion; selected something in the middle between range of pH 1.5-3.5 for stomach pH)?
Would have been nice to understand the variability in endogenous formation link with formula composition (now only distributors and lot numbers are provided in SI, no checks on antioxidant presence, API concentration, solubility, possible interaction with the simulation fluid etc.). Sun Pharmaceuticals tablets are most resistant in this test.
Overall I found the EMA-funded study designs maybe more on point or transparent, papers are apparently in the submission phase. Looking forward to the results to combine insights, anticipating a new chapter in RAIL discussions if the endogenous field gets further increased attention?
I agree with that’s statement ! However the simultaneously drug intake of potentially contaminated drugs leads to
Multicancer development !
We do not have this multicancer or multi skin cancer development / or at least extremely rare/ when the patients do not take potentially contaminated drugs:
Please have in mind that experimental explanations are a some
Kind of static explanations and not dynamic one!
Carcinogenesis is multifaceted condition …simple explanations as it were till now could only lead to drastic increase of skin and other cancer incidence … regarding Globocan:
Even we have a hundreds of papers thamatozing the possible protective positive effect of metformin in experimental
Conditions , we do not have even a single
Patient in advanced stages of cancer which has been cured with metformin !
At the same time we see clinically daily patients doing from
Or within the intake of potentially nitrosamine contaminated drugs like metformin and sitagliptin , Sartans , ranitidine !
This has to be thematised !
Protective behaviour I favour of big pharma could and will be not tolerated anymore !
It is quite obvious that metformin in nitrosating conditions would lead to formation of NDMA.
What is much more interesting is ranitidine case, when digestive conditions lead to formation od NDMA in the absence of nitrate https://www.sciencedirect.com/science/article/pii/S0022354922005214
What is even more intresting is hydrochlorithiazide solid-state degradation leading to it’s nitrosation due to introduction of mechanical stress to crystalline solid, described in this patent:
https://patents.google.com/patent/WO2023161493A1/de
I don’t know if this topic was already discussed here?
Just saw this paper, and there is a lot of truth in what you are saying here. We did our own study like this one last year. We will be presenting a poster at AAPS this fall. This is a much more complex system than one may initially believe. Their nitrite levels were much too high. We did a lot of work to find the correct nitrite levels based on WHO studies on nitrite levels in food & drinking water and found that 0.1-0.4mM was correct.
At a high level, if one just compares gastric conditions with the NAP test, one would presume that nitrosiation is a given.
Hi Jason
Thank you for sharing this information.
Can I ask you please if the presentation at AAPS will be on this October? After the presentation can you please share the content of your study with us?
Much appreciated.
Diana
Yes, it is in October. It is our plan to share the poster here.
