Quantitative Systems Toxicology Modeling Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia Patients

Clin Pharmacol Ther. 2023 Dec 8. doi: 10.1002/cpt.3136. Online ahead of print.ABSTRACTClinical investigation of emvododstat for the treatment of solid tumors was halted after two patients who were heavily treated with other anticancer therapies experienced drug-induced liver failure. However preclinical investigations supported that emvododstat at lower doses might be effective in treating acute myeloid leukemia (AML) and against SARS-CoV-2 as a dihydroorotate dehydrogenase inhibitor. Therefore, a quantitative systems toxicology model, DILIsym, was employed to predict liver safety of the proposed dosing of emvododstat in AML clinical trials. In vitro mechanistic toxicity data of emvododstat and its desmethyl metabolite were integrated with in vivo exposure within DILIsym to predict hepatotoxicity responses in a simulated human population. DILIsym simulations predicted alanine aminotransferase (ALT) elevations observed in prior emvododstat clinical trials in solid tumor patients, but not in the prospective AML clinical trial with the proposed dosing regimens. Exposure predictions based on PBPK modeling suggested that reduced doses of emvododstat would produce clinical exposures that would be efficacious to treat AML. In the AML clinical trial, only 8 patients experienced aminotransferase elevations, all of which were mild (Grade 1), all resolving within a short period of time and no patient showed symptoms of hepatotoxicity, confirming the prospective prediction of liver safet...
Source: Clinical Pharmacology and Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research