Calculating safety margins using total plasma concentration versus unbound plasma concentration - does it make a...

Area of Science:

• Pharmacology and Toxicology
• Drug Development
• Preclinical Safety Assessment

Background:

• Safety margins in non-clinical toxicity studies are crucial for drug development.
• Systemic exposure (AUC) is typically calculated using total plasma concentration (C_p).
• Unbound plasma concentration (C_up) is considered the pharmacologically and toxicologically active component.

Purpose of the Study:

• To evaluate the impact of plasma protein binding differences on safety margin calculations.
• To assess whether incorporating unbound fraction in plasma (fu_p) would alter drug discontinuation decisions.

Main Methods:

• Collected plasma protein binding data for 114 discontinued MSD small molecule compounds.
• Defined a >3-fold difference in unbound fraction in plasma (fu_p) as significant.
• Analyzed toxicity profiles in relation to species-specific plasma protein binding.

Main Results:

• Approximately 3-5% of compounds showed a >3-fold difference in fu_p between non-clinical species (rats, dogs, non-human primates) and humans.
• Incorporating fu_p into safety margin calculations would not have changed the discontinuation outcome for these compounds.

Conclusions:

• Routine use of unbound fraction in plasma (fu_p) for safety margin calculations is not generally warranted.
• fu_p may still be valuable for safety margin assessment on a case-by-case basis.
• The study highlights the importance of considering plasma protein binding but questions its routine application in safety margin calculations.