title: Characterization and validation of an in silico toxicology model to predict the mutagenic potential of drug impurities.
abstract: Control and minimization of human exposure to potential genotoxic impurities found in drug substances and products is an important part of preclinical safety assessments of new drug products. The FDA's 2008 draft guidance on genotoxic and carcinogenic impurities in drug substances and products allows use of computational quantitative structure-activity relationships (QSAR) to identify structural alerts for known and expected impurities present at levels below qualified thresholds. This study provides the information necessary to establish the practical use of a new in silico toxicology model for predicting Salmonella t. mutagenicity (Ames assay outcome) of drug impurities and other chemicals. We describe the model's chemical content and toxicity fingerprint in terms of compound space, molecular and structural toxicophores, and have rigorously tested its predictive power using both cross-validation and external validation experiments, as well as case studies. Consistent with desired regulatory use, the model performs with high sensitivity (81%) and high negative predictivity (81%) based on external validation with 2368 compounds foreign to the model and having known mutagenicity. A database of drug impurities was created from proprietary FDA submissions and the public literature which found significant overlap between the structural features of drug impurities and training set chemicals in the QSAR model. Overall, the model's predictive performance was found to be acceptable for screening drug impurities for Salmonella mutagenicity.
authors.affiliation: Science and Research Staff, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002 USA. luis.valerio@fda.hhs.gov
authors.forename: Luis G
authors.initials: LG
authors.lastname: Valerio
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Cross
mesh_terms: D019295:Computational Biology / Q000379:methods*; D016208:Databases, Factual; D004340:Drug Contamination; D015195:Drug Design; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008954:Models, Biological; D009152:Mutagenicity Tests / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000592:standards; D021281:Quantitative Structure-Activity Relationship; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D014116:Toxicology / Q000379:methods; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D004364:Pharmaceutical Preparations