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

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Abstract
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%.

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