Abstract

Background: Compound A is in development for a life-threatening situation. The “Animal Rule” applies to efficacy, but not to safety assessment, which must be determined in humans. In a pooled safety population involving 150 healthy adult volunteers (NHV), marked elevations of serum liver enzymes were observed in some subjects, suggesting possible liver injury.

Methods: The ALT sub-model within the larger DILIsym™ model was utilized. Key parameters were adjusted to generate simulation results consistent with the data obtained in the human volunteers treated with Compound A.

Results: The predicted percentage of functional hepatocytes lost for the maximum observed ALT level was 3.5%, with a predicted range of 2.5% to 4.5% when simulated human variability, or SimPops™, was included.

Conclusions: The simulations and associated analyses suggest that no subject in the clinical trial likely experienced more than a modest loss of hepatocytes, and that the levels lost were much lower than levels reportedly leading to serious health risks in other scenarios.

American Society for Clinical Pharmacology and Therapeutics (ASCPT), March 5-9, 2013, Indianapolis, Indiana

By Brett A. Howell, Lisl K.M. Shoda, Jeffrey L. Woodhead, Yuching Yang, Scott Q. Siler, Paul B. Watkins