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The role of genetic toxicology in drug discovery and optimization

L L Custer1, K S Sweder

  • 1Department of Genetic Toxicology, Bristol-Myers Squibb, Syracuse NY, 6000 Thompson Rd., Syracuse, NY 13057, USA. laura.custer@bms.com

Current Drug Metabolism
|November 11, 2008
PubMed

Insights

Genetic toxicology testing identifies hazardous drug candidates early in development. This screening prevents the progression of mutagens and manages clastogens, ensuring safer drug development and clinical trials.

Area of Science:

  • Pharmacology and Toxicology
  • Drug Discovery and Development
  • Regulatory Science

Background:

  • Genetic toxicology data serves as a surrogate for long-term carcinogenicity during early drug development.
  • Identifying potentially hazardous drug candidates early is crucial for efficient drug development.
  • Genotoxicity results, combined with animal data, inform decisions on advancing drug candidates to clinical trials.

Purpose of the Study:

  • To outline the critical role of genetic toxicology in identifying and mitigating risks associated with drug candidates.
  • To discuss the impact of mutagenic and clastogenic compounds on drug development timelines and marketability.
  • To review available genotoxicity and carcinogenicity predictive software systems and their application in regulatory decision-making.

Main Methods:

  • Description of mutagenicity and clastogenicity screening tests, including their advantages and disadvantages.
  • Evaluation of commercially available genotoxicity and carcinogenicity predictive software systems.
  • Explanation of the FDA's consensus approach using complementary software packages (e.g., MC4PC, MDL QSAR) for predicting genotoxic or carcinogenic liability.

Main Results:

  • Mutagenic compounds are typically discontinued from development.
  • Clastogenic compounds can lead to unfavorable labeling and impact marketability, often requiring further in vivo relevance studies.
  • The FDA's consensus approach prioritizes certainty in positive predictions, potentially at the cost of sensitivity.

Conclusions:

  • Genetic toxicology screening is essential for the rapid identification and removal of mutagens in drug discovery.
  • Proactive clastogenicity screening allows for better planning of additional toxicity studies, potentially expediting drug progression.
  • Strategic implementation of genetic toxicology testing and predictive software supports informed decision-making in drug development and regulatory submissions.

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