title: Validation of Toxtree and SciQSAR in silico predictive software using a publicly available benchmark mutagenicity database and their applicability for the qualification of impurities in pharmaceuticals.
abstract: The draft ICH M7 guidance (US FDA, 2013) recommends that the computational assessment of bacterial mutagenicity for the qualification of impurities in pharmaceuticals be performed using an expert rule-based method and a second statistically-based (Q)SAR method. The public nonproprietary 6489 compound Hansen benchmark mutagenicity data set was used as an external validation data set for Toxtree, a free expert rule-based SAR software. This is the largest known external validation of Toxtree. The Toxtree external validation specificity, sensitivity, concordance and false negative rate for this mutagenicity data set was 66%, 80%, 74% and 20%, respectively. This mutagenicity data set was also used to create a statistically-based SciQSAR-Hansen mutagenicity model. In a 10% leave-group-out internal cross validation study the specificity, sensitivity, concordance and false negative rate for the SciQSAR mutagenicity model was 71%, 83%, 77% and 17%, respectively. Combining Toxtree and SciQSAR predictions and scoring a positive finding in either software as a positive mutagenicity finding reduced the false negative rate to 7% and increased sensitivity to 93% at the expense of specificity which decreased to 53%. The results of this study support the applicability of Toxtree, and the SciQSAR-Hansen mutagenicity model for the qualification of impurities in pharmaceuticals.
authors: Computational Toxicology Services LLC, P.O. Box 1565, Olney, MD 20830, USA. Electronic address: jfcontrera@verizon.net.
authors: Joseph F
authors: JF
authors: Contrera
mesh_terms: D003198:Computer Simulation; D016208:Databases, Factual; D004340:Drug Contamination; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D012475:Salmonella / Q000187:drug effects / Q000254:growth & development; D012984:Software
chemical_list: D009153:Mutagens
keywords: False negatives; ICH M7; Mutagenicity; Pharmaceuticals; QSAR; Qualification of impurities; SAR; SciQSAR; Toxtree