Absorption, metabolism and excretion of

Area of Science:

• Pharmacology
• Drug Metabolism and Pharmacokinetics
• Biochemistry

Background:

• Emvododstat is a potent dihydroorotate dehydrogenase inhibitor.
• It is under clinical investigation for COVID-19 and acute myeloid leukemia.
• Human metabolism and pharmacokinetics of emvododstat are time-dependent.

Purpose of the Study:

• To evaluate the metabolism and excretion of emvododstat near steady state.
• To characterize emvododstat's pharmacokinetic profile using a repeat-dose study design.
• To identify major circulating and excreted metabolites.

Main Methods:

• A combination of microtracer and high radioactivity doses of ¹⁴C-emvododstat.
• Seven healthy male subjects received daily oral doses for 7 days.
• Radioactivity in plasma, whole blood, urine, and feces was quantified.

Main Results:

• Radioactivity peaked in plasma and whole blood at 6 hours post-dose.
• Mean cumulative recovery was 6.0% in urine and 19.9% in feces by 240 hours.
• Emvododstat, M443, and O-desmethyl emvododstat glucuronide were major circulating components; M474 and O-desmethyl emvododstat were major urinary and fecal metabolites, respectively.

Conclusions:

• The study provides comprehensive absorption, metabolism, and excretion data for emvododstat at near steady-state.
• A repeat-dose microtracer followed by a high-dose strategy effectively addressed challenges with slow metabolism and elimination.
• This approach enables characterization of lipophilic compounds at therapeutically relevant doses.