Bioavailability, Metabolism, and Excretion of [¹⁴C]‐Tazemetostat in Patients With B‐Cell Lymphomas or Advanced Solid Tumors

This open-label, multicenter study (NCT03010982) evaluated the absolute bioavailability, characterized the disposition and metabolism, and investigated the metabolic profile of tazemetostat, a US Food and Drug Administration-approved inhibitor of enhancer of zeste homolog 2, following intravenous and oral [¹⁴C]-labeled and unlabeled tazemetostat in patients with B-cell lymphomas or advanced solid tumors. Patients received oral tazemetostat 800 mg twice daily for 14 days. On Day 15, patients received tazemetostat 800-mg tablets in a fasted state followed by an intravenous microdose of 12 µg [¹⁴C]-tazemetostat. On Day 16, patients received a [¹⁴C]-tazemetostat 800-mg solution with a meal, then continued tazemetostat 800 mg twice daily. Blood, plasma, urine, and fecal samples were collected for pharmacokinetic analyses, and recovery and excretion of the radioactivity of [¹⁴C]-labeled/unlabeled tazemetostat and its metabolites. The median absolute bioavailability was 31.8% (range, 20.2%-49.8%). Notable plasma components were EPZ-6930, unchanged tazemetostat, EPZ006931, and EPZ034163, accounting for 31.8%, 22.4%, 11.0%, and 3.5% of total drug-related exposure, respectively. Recovery of radiolabeled material ranged from 93.2% to 94.7%, with most excreted doses recovered within 48 hours in urine and by 96 hours in feces. Fecal elimination represented the principal route of elimination with a mean of 78.9% of the administered radioactive dose and renal excretion accounted for 15.4%.