Absorption, Metabolism, and Excretion of 14C-Emvododstat Following Repeat Daily Oral Dose Administration in Human Volunteers Using a Combination of Microtracer Radioactivity and High-Radioactivity Doses
article
Emvododstat is a potent inhibitor of dihydroorotate dehydrogenase and is now in clinical development for the treatment of COVID-19 and acute myeloid leukemia. Since the metabolism and pharmacokinetics of emvododstat in humans is time dependent, a repeat-dose study design using a combination of microtracer radioactivity and high-radioactivity doses was employed to evaluate the metabolism and excretion of emvododstat near steady state. Seven healthy male subjects each received 16 mg/0.3 µCi 14C-emvododstat daily oral doses for 6 days followed by a 16 mg/100 µCi high-radioactivity oral dose on Day 7. Following the last 16 mg/0.3 µCi 14C-emvododstat dose on Day 6, total radioactivity in plasma peaked at 6 hours postdose. Following a high-radioactivity oral dose (16 mg/100 µCi) of 14C-emvododstat on Day 7, both whole blood and plasma radioactivity peaked at 6 hours, rapidly declined from 6 hours to 36 hours postdose, and decreased slowly thereafter, with measurable radioactivity at 240 hours postdose. The mean cumulative recovery of the administered dose was 6.0% in urine and 19.9% in feces by 240 hours postdose, and the mean extrapolated recovery to infinity was 37.3% in urine and 56.6% in feces. Similar metabolite profiles were observed after repeat daily microtracer radioactivity oral dosing on Day 6 and after a high-radioactivity oral dose on Day 7. Emvododstat was the most abundant circulating component, and M443 and O-desmethyl emvododstat glucuronide were the major circulating metabolites; M474 was the most abundant metabolite in urine, whereas O-desmethyl emvododstat was the most abundant metabolite in feces.
TNO Identifier
994532
Source
Drug Metabolism and Disposition, 52, pp. 26-34.
Pages
26-34