title: Bacterial mutagenicity screening in the pharmaceutical industry.
abstract: Genetic toxicity testing is used as an early surrogate for carcinogenicity testing. Genetic toxicity testing is also required by regulatory agencies to be conducted prior to initiation of first in human clinical trials and subsequent marketing for most small molecule pharmaceutical compounds. To reduce the chances of advancing mutagenic pharmaceutical candidates through the drug discovery and development processes, companies have focused on developing testing strategies to maximize hazard identification while minimizing resource expenditure due to late stage attrition. With a large number of testing options, consensus has not been reached on the best mutagenicity platform to use or on the best time to use a specific test to aid in the selection of drug candidates for development. Most companies use a process in which compounds are initially screened for mutagenicity early in drug development using tests that require only a few milligrams of compound and then follow those studies up with a more robust mutagenicity test prior to selecting a compound for full development. This review summarizes the current applications of bacterial mutagenicity assays utilized by pharmaceutical companies in early and late discovery programs. The initial impetus for this review was derived from a workshop on bacterial mutagenicity screening in the pharmaceutical industry presented at the 40th Annual Environmental Mutagen Society Meeting held in St. Louis, MO in October, 2009. However, included in this review are succinct summaries of use and interpretation of genetic toxicity assays, several mutagenicity assays that were not presented at the meeting, and updates to testing strategies resulting in current state-of the art description of best practices. In addition, here we discuss the advantages and liabilities of many broadly used mutagenicity screening platforms and strategies used by pharmaceutical companies. The sensitivity and specificity of these early mutagenicity screening assays using proprietary compounds and their concordance (predictivity) with the regulatory bacterial mutation test are discussed.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877-0368, USA. Electronic address: patricia.escobar@boehringer-ingelheim.com.
authors.forename: P A
authors.initials: PA
authors.lastname: Escobar
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877-0368, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Kemper
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877-0368, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tarca
authors.affiliation: AbbVie, Abbott Park, IL 60064-3500, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nicolette
authors.affiliation: Pfizer Global Research and Development, Groton, CT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kenyon
authors.affiliation: Novartis Pharma AG, Werk Klybeck Klybeckstrasse 141, Basel, CH-4057, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Glowienke
authors.affiliation: Amgen Inc., Thousand Oaks, CA 91320-1799, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Sawant
authors.affiliation: Merck Research Laboratories West Point, PA 19486, USA.
authors.forename: J
authors.initials: J
authors.lastname: Christensen
authors.affiliation: Merck Research Laboratories West Point, PA 19486, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Johnson
authors.affiliation: Merck Research Laboratories West Point, PA 19486, USA.
authors.forename: C
authors.initials: C
authors.lastname: McKnight
authors.affiliation: Merck Research Laboratories West Point, PA 19486, USA.
authors.forename: G
authors.initials: G
authors.lastname: Ward
authors.affiliation: Merck Research Laboratories West Point, PA 19486, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Galloway
authors.affiliation: Bristol Myers-Squib, New Brunswick, NJ 08903, USA.
authors.forename: L
authors.initials: L
authors.lastname: Custer
authors.affiliation: Hoffman-La Roche Ltd, Basle, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Gocke
authors.affiliation: AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: O'Donovan
authors.affiliation: Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Braun
authors.affiliation: Merck Research Laboratories West Point, PA 19486, USA; RDS consulting services, Maineville, Ohio. 45039, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Snyder
authors.affiliation: Merck Research Laboratories West Point, PA 19486, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mahadevan
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000235:genetics*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004345:Drug Industry; D006801:Humans; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D009153:Mutagens