1. Academic Validation
  2. Trametinib, a first-in-class oral MEK inhibitor mass balance study with limited enrollment of two male subjects with advanced cancers

Trametinib, a first-in-class oral MEK inhibitor mass balance study with limited enrollment of two male subjects with advanced cancers

  • Xenobiotica. 2014 Apr;44(4):352-68. doi: 10.3109/00498254.2013.831143.
May Y K Ho 1 Michael J Morris Jill L Pirhalla John W Bauman Carolyn B Pendry Keith W Orford Royce A Morrison Donna S Cox
Affiliations

Affiliation

  • 1 Drug Metabolism and Pharmacokinetics, GlaxoSmithKline , King of Prussia, PA , USA .
Abstract

1. This study assessed the mass balance, metabolism and disposition of [(14)C]trametinib, a first-in-class mitogen-activated extracellular signal-related kinase (MEK) inhibitor, as an open-label, single solution dose (2 mg, 2.9 MBq [79 µCi]) in two male subjects with advanced Cancer. 2. Trametinib absorption was rapid. Excretion was primarily via feces (∼81% of excreted dose); minor route was urinary (∼19% of excreted dose). The primary metabolic elimination route was deacetylation alone or in combination with hydroxylation. Circulating drug-related component profiles (composed of parent with metabolites) were similar to those found in elimination together with N-glucuronide of deacetylation product. Metabolite analysis was only possible from <50% of administered dose; therefore, percent of excreted dose (defined as fraction of percent of administered dose recovery over total dose recovered in excreta) was used to assess the relative importance of excretion and metabolite routes. The long elimination half-life (∼10 days) favoring sustained targeted activity was important in permitting trametinib to be the first MEK Inhibitor with clinical activity in late stage clinical studies. 3. This study exemplifies the challenges and adaptability needed to understand the metabolism and disposition of an Anticancer agent, like trametinib, with both low exposure and a long elimination half-life.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-148507
    98.81%, Trametinib代谢物
    MEK