The authors analysis of the chemical and manufacturing aspects, emphasizing the difficulties in meeting non-MW-corrected AI criteria compared to the practicality of MW-corrected criteria compliance, is thought-provoking. This is an important topic that warrants more attention and discussion in our field.
It is an improvement value-wise, but probably often not the preferred option compared to other AI derivatisation options. Readacross would also allow MW-corrections, so the magnitude of difference between initial AI and MW corrected AI does not differ in the end, meaning that the MW correction unfortunately doesn’t lower the relative gap between readacross and CPCA e.g.:
N-nitroso-fluoxetine: 100 ng/day → 297 ng/day (via MW correction and ICH M7 most robust study (Rivenson 1988), most sensitive tumor site/tissue approach) = factor 3 correction
N-nitroso-fluoxetine: CPCA cat. 1 18 ng/day → 55 ng/day = factor 3 correction (when making abstraction of 26.5 ng/day CPCA cat. 1 in US)
I’m also wondering whether the CPCA MW-rules would be expected to be capped (just like Q&A 22 capping on LTL). Could you, due to very high MW (exceptional though), jump categories and have a MW-corrected CPCA cat. 1 above 100 ng/day? What if MW corrections can be developed for other categories, if and how to cap?
Probably for CPCA category 2 we can also already think about a MW correction mechanism and category improvement (but this should probably go hand in hand with optimization of (de-)activating features and industry verifications on the CPCA design).
CPCA category 1:
18 ng/day for MW <120 Da
MW >120 Da: Fine 2023 rule: 163 pmol/day x MW nitrosamine (ng/pmol) = AI (ng/day) (with or without a capping at 100 ng/day?)
CPCA category 2:
150 ng/day based on NDMA (145 ng/day) and NNK (182 ng/day) readacross.
MW > 200 Da: 880 pmol/day x MW nitrosamine (ng/pmol) = AI (ng/day) (with or without a capping at 400 ng/day?) (Capping here should mean extra capping on Q&A might be a bridge too far?)
CPCA category 3:
To be evaluated when transparency on design of CPCA and 84 molecules and their MW?
Piperidine and pyrrolidine corrections to be optimized?
AS IS: N-nitroso group in a 5- or 6-membered ring: CPCA score + 2
TO BE: N -nitroso group in a 5- or 6-membered ring not identifying as a piperidine or pyrrolidine: CPCA score +2; N -nitroso group in a piperidine or pyrrolidine ring: CPCA score +3
CPCA category 4-5
To be evaluated when transparency on design of CPCA and 84 molecules
MW corrections incompatible with TTC concept (category 4)