Transitioning to composite bacterial mutagenicity models in ICH M7 (Q)SAR analyses.

Transitioning to composite bacterial mutagenicity models in ICH M7 (Q)SAR analyses. Regul Toxicol Pharmacol. 2019 Oct 03;:104488 Authors: Landry C, Kim MT, Kruhlak NL, Cross KP, Saiakhov R, Chakravarti S, Stavitskaya L Abstract The International Council on Harmonisation (ICH) M7(R1) guideline describes the use of complementary (quantitative) structure-activity relationship ((Q)SAR) models to assess the mutagenic potential of drug impurities in new and generic drugs. Historically, the CASE Ultra and Leadscope software platforms used two different statistical-based models to predict mutations at G-C (guanine-cytosine) and A-T (adenine-thymine) sites, to comprehensively assess bacterial mutagenesis. In the present study, composite bacterial mutagenicity models covering multiple mutation types were developed. These new models contain more than double the number of chemicals (n = 9254 and n = 13,514) than the corresponding non-composite models and show better toxicophore coverage. Additionally, the use of a single composite bacterial mutagenicity model simplifies impurity analysis in an ICH M7 (Q)SAR workflow by reducing the number of model outputs requiring review. An external validation set of 388 drug impurities representing proprietary pharmaceutical chemical space showed performance statistics ranging from of 66-82% in sensitivity, 91-95% in negative predictivity and 96% in coverage. This effort represents a major enhancement...
Source: Regulatory Toxicology and Pharmacology : RTP - Category: Toxicology Authors: Tags: Regul Toxicol Pharmacol Source Type: research