Computational Toxicologist US Food and Drug Administration Silver Spring, Maryland
This presentation will provide an overview of the development and regulatory implementation of the Carcinogenic Potency Categorization Approach (CPCA), a recently published structure-activity relationship (SAR) model for determining acceptable intake limits for nitrosamine impurities in pharmaceuticals. SAR models can be used to make a prediction of a chemical’s toxicity based solely on its structure. The widespread emergence of nitrosamines as impurities in pharmaceuticals, combined with the lack of associated experimental safety data in many cases, led to the application of SAR approaches to predict carcinogenic risk and determine acceptable intake limits. Most recently, FDA and other drug regulatory authorities published the CPCA, which uses knowledge of activating and deactivating nitrosamine substructural patterns to predict carcinogenic potency by consideration of metabolic activation through an alpha-hydroxylation pathway. The CPCA was developed collaboratively by regulatory authorities using a training dataset of 81 nitrosamines with quantitative and/or qualitative carcinogenic potency data supplemented with knowledge of chemical reactivity and metabolism. Efforts are now underway by external groups to collate new experimental safety data for nitrosamine impurities and to use these data in combination with computational methods to propose refinements to CPCA structural features and properties and inform potential future updates to the model.
Learning Objectives:
Understand why structure-activity relationship approaches are used to determine acceptable intake limits for nitrosamine impurities in pharmaceuticals
Be familiar with how the CPCA was developed, its practical application, its performance characteristics, and its structural limitations
Have awareness of ongoing efforts to leverage newly-generated experimental data and computational calculations to inform future potential CPCA model refinements
