Trametinib, a first-in-class oral MEK inhibitor mass balance study with limited enrollment of two male subjects with advanced cancers.
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Ho MY, Morris MJ, Pirhalla JL, Bauman JW, Pendry CB, Orford KW, Morrison RA, Cox DS
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. Epub 2013 Aug 23.
- PubMed ID
- 23971497 [ View in PubMed]
- 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 microCi]) in two male subjects with advanced cancer. 2. Trametinib absorption was rapid. Excretion was primarily via feces ( approximately 81% of excreted dose); minor route was urinary ( approximately 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 ( approximately 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Trametinib Dual specificity mitogen-activated protein kinase kinase 1 Protein Humans YesInhibitorDetails - Drug Reactions
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