Quantitative Systems Toxicology (QST) Modeling Using DILIsym Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia (AML) Patients

Conference: ASCPT
Software: DILIsym®


Clinical investigation of emvododstat for the treatment of solid tumors was terminated after two patients who were heavily treated with other anticancer therapies experienced drug induced liver failure. Subsequent investigations supported that emvododstat might be effective in treating AML at lower doses than administered in the solid tumor clinical trials. A QST model, DILIsym, was employed to predict liver safety of the proposed dosing of emvododstat in AML clinical trials.


A PBPK model for emvododstat and its desmethyl metabolite was developed. In vitro assays were performed to assess effects of emvododstat and its desmethyl metabolite on bile acid transport, mitochondrial function, and oxidative stress (ROS). These data were integrated with in vivo exposure within DILIsym to predict hepatotoxicity responses in a simulated human population.


DILIsym simulations predicted the ALT elevations observed in prior emvododstat clinical trials for solid tumors, but ALT elevations were not predicted to occur with the emvododstat dosing proposed for the AML clinical trials. The modeling enabled regulatory approval to proceed with the AML clinical trial where significant liver safety concerns were not evident.


  1. DILIsym Services Division, Simulations Plus Inc. Research Triangle Park, NC
  2. PTC Therapeutics, Inc., South Plainfield, NJ
  3. UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, NC

Kyunghee Yang, Ronald Kong, Pius Maliakal, Robert Spiegel, John D. Baird, Kylie O’Keefe, Paul B. Watkins, Brett A. Howell

American Society for Clinical Pharmacology and Therapeutics (ASCPT) Annual Meeting, March 22-24, 2023, Atlanta, GA