PII-036 - MASS BALANCE AND METABOLITE IDENTIFICATION OF VALEMETOSTAT AFTER A SINGLE ORAL ADMINISTRATION IN HEALTHY MALE SUBJECTS.

S. Inaba¹, M. Kazui¹, T. Shimizu¹, T. Craveiro², M. Abutarif³; ¹Daiichi Sankyo, Tokyo, Japan, ²Gilead Sciences, Morris Plains, NJ, USA, ³Daiichi Sankyo, Basking Ridge, NJ, USA.

Background: Valemetostat is an orally administered dual inhibitor of enhancer of zeste homolog (EZH) 1 and EZH2 being investigated for the treatment of various types of cancers, including non-Hodgkin lymphomas and solid tumors. The current study was designed to assess pharmacokinetics, metabolism, and excretion of valemetostat in humans after oral administration.

Methods: Eight healthy male subjects received a single oral dose of [14C]valemetostat tosylate (as approximately 200 mg/150 μCi valemetostat) in this open-label Phase 1 study. Blood, urine and feces samples were collected up to 360 h, assayed for radioactivity, and analyzed using Radio-HPLC and LC-MSn to confirm metabolite profiling.

Results: Most of radioactivity (86.7% of dose) was recovered up to 96 h post-dose. By 360 h, 16% and 80% of dose were excreted into urine and feces, respectively. Valemetostat was rapidly absorbed (median tmax of 2.5 h) and eliminated with a half-life of 12.7 h. Blood/plasma ratios observed for the AUC and Cmax was 0.54 and 0.57, respectively. Valemetostat (55% of total radioactivity AUC) and oxidative metabolite (CALZ-1809a) were the main components in plasma. Seven metabolites were found each in urine and feces, with valemetostat as the major component (10% (of dose) in urine and 65% in feces). CALZ-1809a was recovered in urine (0.8%) and feces (5.6%). Six oxidative metabolites other than CALZ-1809 and three conjugated metabolites were detected, but minor amounts of them (≤ 1.75% each) were recovered in urine and feces.

Conclusion: The radioactivity was mainly excreted into feces as parent drug after oral administration of [14C]valemetostat. Valemetostat and oxidative metabolite, CALZ-1809a are major component in plasma. Oxidative and conjugated metabolites were also observed in urine and feces.