Abstract B160: Assessing human absorption, metabolism, routes of excretion and the contribution of intestinal metabolism to the oral clearance of cobimetinib, a MEK inhibitor.
Authors: Choo Edna , Takahashi Ryan , Rooney Isabelle , Gates Mary , Deng Alan , Musib Luna 
Published: August 2014

Cobimetinib (GDC-0973; XL518) is a potent and highly selective inhibitor of MEK1/2, currently in clinical development as an anticancer agent. The purpose of this investigation was to determine the human absorption, metabolism and routes of excretion of cobimetinib after oral administration to healthy human subjects as well as to assess the contribution of intestinal metabolism to the oral clearance (CL) of cobimetinib. A single 20 mg [14C]-cobimetinib (200 μCi) oral dose was administered to six healthy volunteers. Blood, urine and feces were collected for determination of levels of cobimetinib and cobimetinib-related radioactivity in each matrix. In separate healthy subject study, the CL and bioavailability (F) of cobimetinib were determined from an open-label, 2-way crossover absolute bioavailability study after intravenous (IV; 2 mg) and oral (20 mg) administration of cobimetinib to healthy volunteers (n=20; 19 completed). Approximately 94% of the [14C] dose was recovered in excreta. Cobimetinib was predominantly excreted in feces with 77% of radioactivity recovered in the feces vs. 18% of the dose recovered in urine. Cobimetinib was extensively metabolized, as only 1.6% and 6.6% of unchanged cobimetinib was observed in urine and feces, respectively. The % of the cobimetinib dose absorbed was 88% (Fa), based on the sum of % total radioactivity identified in urine and the % of total metabolites in feces. Unchanged cobimetinib and 5 metabolites; oxidative, glucuronide and glycine conjugate metabolites were identified in plasma. After IV and oral administration of cobimetinib, hepatic extraction (EH) of cobimetinib was 13% and the F of cobimetinib was 46%. Based on the % of cobimetinib absorbed and, if only EH contributed to the CL of cobimetinib, the predicted F (F = Fa*Fint*FH) would be 76%. The lower observed F of 46% suggested that after oral administration, 43% of cobimetinib undergoes extra-hepatic CL, likely via intestinal metabolism. Furthermore, comparison of plasma metabolite profiles after IV and oral dosing showed significantly higher (2 to 5-fold) metabolite to parent ratios after oral dosing, consistent with the contribution of intestinal metabolism. Additionally, using physiologically based pharmacokinetic modeling the IV pharmacokinetic profile of cobimetinib was well described using the observed IV CL. However, the oral PK profile was best described by the addition of intestinal CL. The collective data confirm that cobimetinib is extensively metabolized and excreted in feces after oral dosing. There appears to be a greater contribution of intestinal metabolism than hepatic metabolism to the overall oral CL of cobimetinib.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B160.

Citation Format: Edna Choo, Ryan Takahashi, Isabelle Rooney, Mary Gates, Alan Deng, Luna Musib. Assessing human absorption, metabolism, routes of excretion and the contribution of intestinal metabolism to the oral clearance of cobimetinib, a MEK inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B160.