Scholarlink

Introduction <p>Valemetostat 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.</p> Methods <p>Eight healthy participants received a single 200-mg oral dose of [<sup>14</sup>C]-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.</p> Results <p>Mean cumulative recovery of administered radioactivity was 95.3% by 360&#xa0;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 (&gt;&#xa0;94%) at clinically relevant concentrations, with a higher affinity to AAG than to HSA.</p> Conclusion <p>Valemetostat 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月10日

查看全文
  • Masaya Tachibana,
  • Nicholas Siebers,
  • Thuy Vu Craveiro,
  • Miho Kazui,
  • Tomoko Ikeda,
  • Takako Shimizu,
  • Shinichi Inaba,
  • Malaz A. Abutarif

摘要

Introduction

Valemetostat 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.

Methods

Eight 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.

Results

Mean 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.

Conclusion

Valemetostat 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.