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Quantitative assessment of cumulative carcinogenic risk for multiple genotoxic impurities in a new drug substance

Joel P Bercu1, Wherly P Hoffman, Cindy Lee

  • 1Eli Lilly and Company, Lilly Research Laboratories, 2001 W. Main Street, Greenfield, IN 46140, USA. jpbercu@lilly.com

Regulatory Toxicology and Pharmacology : RTP
|June 14, 2008
PubMed

Insights

Controlling multiple genotoxic impurities to the threshold of toxicological concern (TTC) slightly increases cancer risk. However, even with correlated potencies, the risk remains manageable, aiding pharmaceutical risk assessment.

Area of Science:

  • Pharmaceutical Development
  • Toxicology
  • Risk Assessment

Background:

  • Minimizing carcinogenic potential of new drug substances (NDS) is critical in pharmaceutical development.
  • Genotoxicity and carcinogenicity testing of NDS and impurities is essential.
  • The threshold of toxicological concern (TTC) is used for single mutagenic impurities lacking carcinogenicity data.

Purpose of the Study:

  • To assess the impact of multiple genotoxic impurities on cancer risk in NDS.
  • To evaluate cancer risk when multiple impurities are controlled at the TTC.
  • To analyze the effect of correlated impurity potencies on overall cancer risk.

Main Methods:

  • Replication of single genotoxic compound analysis.
  • Statistical simulations for mixtures of genotoxic compounds.
  • Probabilistic analysis of cancer risk.

Main Results:

  • An increase in cancer risk was observed when multiple genotoxic impurities were controlled to the TTC.
  • The observed increase in cancer risk was small, considering conservative TTC assumptions.
  • Structurally similar compounds with correlated potencies did not negatively impact cancer risk.

Conclusions:

  • Managing multiple genotoxic impurities at the TTC leads to a small, manageable increase in cancer risk.
  • Probabilistic analysis provides valuable insights for risk management decisions regarding genotoxic impurities.
  • The findings support informed decision-making for controlling trace levels of multiple genotoxic impurities in drug substances.

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