PII-124 - METABOLISM AND DISPOSITION OF [14C]-ONC201 (DORDAVIPRONE) IN HEALTHY ADULT PARTICIPANTS

Y. Teffera¹, T. Tippin¹, F. de Castro², J. Batonga², S. Faison², M. Anderson¹, M. Mullin¹, A. Bartkus¹, M. Morrison¹, O. Naderer¹; ¹Chimerix, Inc., ²Certara Strategic Consulting.

Background: ONC201 (dordaviprone) is a novel, small molecule imipridone with demonstrated antitumor effects in glioma patients. The inactive, N-dealkylation metabolite, ONC207, was the predominant metabolite formed in vitro in human, dog, and rat hepatocytes. However, in vivo in rats, ONC207 was a minor metabolite due to subsequent metabolism to other products. This study evaluated the absorption, metabolism, and excretion of ONC201 in humans.

Methods: Six healthy male participants received a single 625 mg (100 µCi) dose of [14C]-ONC201. Blood, plasma, urine and feces were collected post dose throughout confinement (up to 288 h) and analyzed by liquid scintillation counting. Metabolite profiles were evaluated using liquid chromatography (LC) with radioactivity detection, and metabolite identification was assessed by LC with tandem mass spectroscopy.

Results: All participants were included in the analysis population. Concentrations of drug-derived radioactivity in blood and plasma peaked 1-hour postdose and were below the limit of quantitation by 72 to 96 h postdose. Low distribution of radioactivity in blood cells was observed. Overall recovery of excreted radioactivity was 90.9% ± 5.25%, with 70.6% ± 5.82% of the radioactivity recovered in urine and 20.3% ± 1.72% in feces. Based on urine recovery, ≥70% of the ONC201 dose was absorbed. In plasma the major circulating compounds were ONC201 and ONC207, contributing 32.8%+7.19 and 31.5%+7.03% of the total radioactivity (TRA) AUC, respectively. Of the 19 metabolites identified in plasma, no other single metabolite contributed >10% of the TRA AUC. In urine and feces, unchanged ONC201 was a minor component ( < 0.3%), with 24 metabolites identified in urine and 17 metabolites identified in feces. The primary metabolic pathways for ONC201 were oxidative. Consistent with hepatocyte studies, the major human metabolite was ONC207. In contrast to rats, further oxidation of ONC207 with conjugation and excretion of conjugates into feces via bile represented minor pathways in humans.

Conclusion: [14C]-ONC201 was well-absorbed after oral administration and largely cleared as oxidative metabolites in urine and feces. The major circulating metabolite was ONC207.