Injection-Site Sarcomas in Rodent Carcinogenicity Studies: Human Relevance and Labeling Implications.

Area of Science:

• Toxicology
• Pharmacology
• Oncology

Background:

• The two-year rodent carcinogenicity bioassay is a standard for evaluating drug carcinogenic potential.
• The subcutaneous (SC) route is frequently used for parenteral drug administration in these studies.
• Rodents exhibit a species-specific susceptibility to injection-site sarcomas induced by chronic inflammation.

Purpose of the Study:

• To evaluate the relevance of rodent injection-site sarcomas in carcinogenicity bioassays.
• To assess the impact of the subcutaneous route on study outcomes.
• To recommend alternative administration routes for rodent carcinogenicity studies.

Main Methods:

• Review of existing literature on rodent carcinogenicity studies.
• Analysis of case studies involving marketed drugs (e.g., pegvisomant, insulin glargine).
• Comparison of rodent responses to human responses at injection sites.

Main Results:

• Repeated SC injections or inert material implantation in rodents commonly induce injection-site sarcomas.
• These sarcomas arise from a species-specific response to chronic inflammation and fibroblastic proliferation.
• Humans rarely develop such tumors at injection sites, indicating limited predictive value for human risk.
• Marketed drugs have shown SC-induced sarcomas in rodents without posing a human risk.

Conclusions:

• The subcutaneous route in rodent carcinogenicity studies often yields findings not relevant to human risk due to species-specific responses.
• Practical challenges in dosing and the phenomenon's species-specific nature complicate long-term rodent studies.
• Avoidance of the SC route in rodent carcinogenicity bioassays is recommended whenever feasible to enhance study relevance.