Seeking feedback on rationalizing AI limits for an oral solid NDSRI that is rapidly metabolized by blood esterases to form the active moiety and a non-active portion that contains the nitrosamine moiety. The potency category for the NDSRI is 100ng/day whereas the potency category for the non-active/residual nitrosamine-containing portion is 1500ng/day. Given the rapid metabolism of the NDSRI, it seems appropriate to adjust the acceptable daily intake limit of the NDSRI based on the form that is quickly formed and most abundant in the blood stream (i.e., the non-active/residual nitrosamine-containing molecule). Because the non-active/residual nitrosamine-containing portion has a MW that is 15% that of the NDSRI, it suggests a substantially higher limit for the NDSRI could be supported (e.g., as much as 6 x 1,500ng/day). Any advice/considerations/thoughts surrounding this approach?
If your NDSRI is an ester, you can justify the limit based on the free acid in view of the fact that blood and in many other organs, esterase is common. It also helps if the free acid is the metabolite of the drug.
3 Likes
very interesting and nice approach Aloka.
Have you ever tried this? and if yes, which was the reaction of the authorities? was it accepted?
Christos
1 Like
Tried for one. Gave a lot of literature references. The jury is still out.
3 Likes