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

Abstract

1. This study assessed the mass balance, metabolism and disposition of [¹⁴C]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.

• ADME
• human metabolites
• long elimination half-life
• oncology
• trametinib

Acknowledgements

All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. We acknowledge Dr Daniele Ouellet for scientific discussion and advice; Dr Geoff Badman for the synthesis and purification of [¹⁴C] trametinib; Ms Cynthia Rominger for providing the in vitro pharmacological activities of the metabolites; Ms Sherry Wang and Ms Ciara Rodgers for bioanalytical data analysis; Ms Jessica Madden for the in vitro blood and plasma investigation; Dr. Liangfu Chen and Ms Marta Johnson for in vitro NAT enzymology investigation; Mr Ernest Schburt, Dr Igo Goljer and Ms Janine Rogers for NMR data of the metabolite structure elucidation; Dr Stephen Castillano for consultation of metabolite structure elucidation; Dr Dennis Heller for consultation of dosimetry and radiological exposure; GSK Human ADME Forum for consultation; and Ms Veronique Fauve of ICON Clinical, for the clinical in-life operation support. Julienne Orr from Modoc Research Services provided writing assistance and Dr Yanli Deng, Mr. Andy Harrel, Dr Harma Ellens and Ms Mary Richardson provided additional editorial support for this manuscript.