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 [(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.

Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours

“…Symbols denote male (triangles) and female (circles) subjects followed by a protracted elimination phase likely reflective of slow elimination from deep compartments. It has been shown that parent trametinib, but not metabolites, preferentially distributes to red blood cells and this accounts for the initial rapid distribution phase [22] and is supportive of the observation that following a single i.v. dose, parent trametinib accounts for 52% (range 43%-63%) of the total radioactivity in plasma.…”

Computational Prediction of the Site(s) of Metabolism and Binding Modes of Protein Kinase Inhibitors Metabolized by CYP3A4

“…1). Information on the SOMs of the KIs metabolized by human CYP3A4 was obtained from the published literature and from product information (Glivec, 2001;Iressa, 2003;McKillop et al, 2004;Gschwind et al, 2005;Ling et al, 2006;Nexavar, 2006;Sutent, 2006;Tarceva, 2006;Sprycel, 2007;Tykerb, 2007;Christopher et al, 2008b;Minami et al, 2008;Tasigna, 2008;Shilling et al, 2010;Votrient, 2010;Castellino et al, 2012;Speed et al, 2012;Zelboraf, 2012;Caprelsa, 2013;Deng et al, 2013;Jakavi, 2013;Stivarga, 2013;Tafinlar, 2013;Xalkori, 2013;Bosulif, 2014;Ding, 2014;Dowty et al, 2014;Ho et al, 2014;Iclusig, 2014;Mekinist, 2014;Smith et al, 2014;Goldinger et al, 2015;Imbruvica, 2015;Johnson et al, 2015;Lacy et al, 2015;Loi et al, 2015;Scheers et al, 2015;Xeljanz, 2015;Zydelig, 2015;Abbas and Hsyu, 2016;Cotellic, 2016;Dickinson et al, 2016;Dubbelman et al, 2016;Lenvima, 2016;…”

Dabrafenib in combination with trametinib for the treatment of metastatic melanoma

“…In two patients given a dose of 2 mg of [(14)C]trametinib, 81% was detected in the feces and 19% was found in the urine. Trametinib is primarily metabolized via deacetylation [15].…”