title: Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: A case study using aromatic amine mutagenicity.
abstract: Statistical-based and expert rule-based models built using public domain mutagenicity knowledge and data are routinely used for computational (Q)SAR assessments of pharmaceutical impurities in line with the approach recommended in the ICH M7 guideline. Knowledge from proprietary corporate mutagenicity databases could be used to increase the predictive performance for selected chemical classes as well as expand the applicability domain of these (Q)SAR models. This paper outlines a mechanism for sharing knowledge without the release of proprietary data. Primary aromatic amine mutagenicity was selected as a case study because this chemical class is often encountered in pharmaceutical impurity analysis and mutagenicity of aromatic amines is currently difficult to predict. As part of this analysis, a series of aromatic amine substructures were defined and the number of mutagenic and non-mutagenic examples for each chemical substructure calculated across a series of public and proprietary mutagenicity databases. This information was pooled across all sources to identify structural classes that activate or deactivate aromatic amine mutagenicity. This structure activity knowledge, in combination with newly released primary aromatic amine data, was incorporated into Leadscope's expert rule-based and statistical-based (Q)SAR models where increased predictive performance was demonstrated.
authors.affiliation: AstraZeneca, Mölndal, Sweden.
authors.forename: Ernst
authors.initials: E
authors.lastname: Ahlberg
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Amberg
authors.affiliation: Toxicology Solutions, San Diego, CA, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Beilke
authors.affiliation: Leadscope, Columbus, OH, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bower
authors.affiliation: Leadscope, Columbus, OH, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Cross
authors.affiliation: Bristol-Myers Squibb Co., New Brunswick, NJ, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Custer
authors.affiliation: Genentech, South San Francisco, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Ford
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Jacky
authors.initials: J
authors.lastname: Van Gompel
authors.affiliation: GlaxoSmithKline, Ware, UK.
authors.forename: James
authors.initials: J
authors.lastname: Harvey
authors.affiliation: National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Honma
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jolly
authors.affiliation: European Commission Joint Research Centre, Ispra, Italy.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Joossens
authors.affiliation: Vertex, Boston, MA, USA.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Kemper
authors.affiliation: Pfizer, Groton, CT, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kenyon
authors.affiliation: FDA Center for Drug Evaluation and Research, Silver Spring, MD, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kruhlak
authors.affiliation: Bayer HealthCare, Berlin, Germany.
authors.forename: Lara
authors.initials: L
authors.lastname: Kuhnke
authors.affiliation: Bristol-Myers Squibb Co., New Brunswick, NJ, USA.
authors.forename: Penny
authors.initials: P
authors.lastname: Leavitt
authors.affiliation: Pfizer, Groton, CT, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Naven
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Neilan
authors.affiliation: Leadscope, Columbus, OH, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Quigley
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Shuey
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Spirkl
authors.affiliation: FDA Center for Drug Evaluation and Research, Silver Spring, MD, USA.
authors.forename: Lidiya
authors.initials: L
authors.lastname: Stavitskaya
authors.affiliation: AstraZeneca, Cheshire, England, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Teasdale
authors.affiliation: GlaxoSmithKline, Ware, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: White
authors.affiliation: Bayer HealthCare, Berlin, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Wichard
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Zwickl
authors.affiliation: Leadscope, Columbus, OH, USA. Electronic address: gmyatt@leadscope.com.
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Myatt
mesh_terms: D000588:Amines / Q000737:chemistry / Q000145:classification / Q000633:toxicity*; D000818:Animals; D003198:Computer Simulation; D057225:Data Mining / Q000379:methods*; D016208:Databases, Factual; D006801:Humans; D051188:Knowledge Bases; D008958:Models, Molecular; D015394:Molecular Structure; D016296:Mutagenesis; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000737:chemistry / Q000145:classification / Q000633:toxicity*; D010363:Pattern Recognition, Automated; D021281:Quantitative Structure-Activity Relationship; D018570:Risk Assessment
chemical_list: D000588:Amines; D009153:Mutagens
keywords: (Q)SAR; Aromatic amines; ICH M7; Mutagenicity; Pharmaceutical impurities; SAR fingerprint