Developing Structure-Activity Relationships for -Nitrosamine Activity.

The detection of -nitrosodimethylamine (NDMA) in several marketed drugs led regulatory agencies to require that -nitrosamine risk assessments be performed on all marketed medical products [EMA/351053/2019 rev 1 (2019)]. Regulation of -nitrosamine impurity levels in pharmaceutical drug substances and products is described in the ICH M7(R1) guideline where they are referred to as "cohort-of-concern" compounds as several are potent rodent carcinogens [Kroes . 2004]. EMA, U.S. FDA and other regulatory agencies have set provisional acceptable daily intake limits for nitrosamines calculated from rodent carcinogenicity TD values for experimentally measured nitrosamines or the measured TD values of close analogs. The class-specific limit can be adjusted based upon a structure activity relationship analysis (SAR) and comparison with analogs having established carcinogenicity data [EMA/369136/2020, (2020)]. To investigate whether improvements in SARs can more accurately predict -nitrosamine carcinogenic potency, an ad hoc workgroup of 23 companies and universities was established with the goals of addressing several scientific and regulatory issues including: reporting and review of -nitrosamine mutagenicity and carcinogenicity reaction mechanisms, collection and review of available, public relevant experimental data, development of structure-activity relationships consistent with mechanisms for prediction of nitrosamine carcinogenic potency categories, and improved methods for calculating acceptable intake limits for -nitrosamines based upon mechanistic analogs. Here we describe this collaboration and review our progress to date towards development of mechanistically based structure-activity relationships. We propose improving risk assessment of -nitrosamines by first establishing the dominant reaction mechanism prior to retrieving an appropriate set of close analogs for use in read-across exercises.