Successful drug development despite adverse preclinical findings part 2: examples

Area of Science:

• Pharmacology
• Toxicology
• Drug Development

Background:

• Adverse preclinical findings (APFs) require careful management during drug development.
• Understanding the mode of action (MoA) and human relevance is key to risk assessment.

Purpose of the Study:

• To illustrate the process of addressing unexpected APFs in drug candidate toxicity studies.
• To emphasize risk characterization and evaluation of human relevance for various APFs.

Main Methods:

• Case discussions of unexpected APFs from toxicity studies.
• Evaluation of risk based on MoA and species-specific toxicological models.
• Review of known issues like phospholipidosis and PPAR agonist carcinogenicity.

Main Results:

• Severe APFs like retinal toxicity may have low human relevance, while minor findings (e.g., vasculitis) can be significant.
• Rodent models have limitations for endocrine APFs, and non-rodents for cardiac effects.
• Liver and kidney toxicities are common but often manageable; novel findings require thorough investigation.

Conclusions:

• APFs, including genotoxicity and reproductive toxicity, necessitate case-by-case evaluation.
• The safety paradigm for peroxisome proliferator-activated receptor (PPAR) agonists has evolved.
• Effective management of APFs is critical for successful drug development and patient safety.