Pharmacokinetics, metabolism, and excretion of [14C]-valemetostat in healthy male participants, and in vitro plasma protein binding

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IntroductionValemetostat tosylate (valemetostat) is an oral, selective, dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1. This article reports findings on the mass balance and pharmacokinetics of valemetostat in a phase I study; valemetostat metabolite identification in plasma, urine, and fecal samples; and plasma-protein-binding of valemetostat in vitro.MethodsEight healthy participants received a single 200-mg oral dose of [14C]-valemetostat under fasting conditions. Blood, urine, and feces samples were collected to determine total radioactivity and/or unchanged valemetostat, and for metabolite identification. The binding of valemetostat 600–10,000 ng/mL to plasma, 4% human serum albumin (HSA), and 0.1% alpha-1-acid glycoprotein (AAG) was assessed in vitro.ResultsMean cumulative recovery of administered radioactivity was 95.3% by 360 h post-dose, with a mean recovery of 15.6% in urine and 79.8% in feces. Valemetostat accounted for the most radioactivity in the excreta, at 10% and 64.9% of the administered dose in the urine and feces, respectively. CALZ-1809a was the most abundant metabolite, present in all biological samples, and accounted for 5.6% of total radioactivity in the feces. Valemetostat was minimally associated with red blood cells, with a blood-to-plasma total radioactivity ratio of 0.54. In vitro, valemetostat was highly plasma-bound (> 94%) at clinically relevant concentrations, with a higher affinity to AAG than to HSA.ConclusionValemetostat was rapidly absorbed into the systemic circulation, mainly excreted via the biliary/fecal route, primarily metabolized by CYP3A enzymes to CALZ-1809a, and highly bound to plasma proteins, with a greater affinity to AAG than HSA in vitro.