Threshold of toxicological concern (TTC) for developmental and reproductive toxicity of anticancer compounds

Area of Science:

• Pharmacology
• Toxicology
• Drug Development

Background:

• Pharmaceutical companies face challenges in early drug development for anticancer compounds due to modified preclinical toxicology testing requirements.
• Limited data packages can impact product quality in multi-product manufacturing facilities for life-saving cancer therapies.

Purpose of the Study:

• To establish an endpoint-specific threshold of toxicological concern (TTC) for developmental and reproductive toxicity (DART) specifically for anticancer compounds.
• To provide a safety threshold that balances accelerated drug development with the protection against DART.

Main Methods:

• A comprehensive database of over 300 no-observed adverse effect levels (NOAELs) for DART was compiled for 108 anticancer compounds.
• Statistical analysis was performed to determine the 5th percentile NOAEL for DART.
• Standard uncertainty factors and a 60 kg human bodyweight were applied to derive a human exposure threshold.

Main Results:

• The 5th percentile NOAEL for DART was determined to be 0.005 mg/kg/day (300 μg/day).
• This resulted in a protective human exposure threshold of 3 μg/day for developmental and reproductive toxicity.
• Similar TTC values were observed for both direct-acting and indirect-acting anticancer compounds.

Conclusions:

• The established TTC is protective for developmental and reproductive toxicity in highly potent anticancer compounds.
• This threshold supports modified preclinical testing requirements, potentially accelerating the availability of life-saving cancer treatments.
• The findings are applicable to a broad range of anticancer agents, irrespective of their mechanism of action.