Metabolism and Disposition of Oral Dabrafenib in Cancer Patients: Proposed Participation of Aryl Nitrogen in Carbon-Carbon Bond Cleavage via Decarboxylation following Enzymatic Oxidation

Abstract

A phase I study was conducted to assess the metabolism and excretion of [ 14 C]dabrafenib (GSK2118436; N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt), a BRAF inhibitor, in four patients with BRAF V600 mutation-positive tumors after a single oral dose of 95 mg (80 mCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-highperformance liquid chromatography-tandem mass spectrometry methods, 2) plasma and blood radioactivity, 3) urinary and fecal radioactivity, and 4) metabolite profiling. Results showed the mean total recovery of radioactivity was 93.8%, with the majority recovered in feces (71.1% of administered dose). Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine. Dabrafenib is metabolized primarily via oxidation of the t-butyl group to form hydroxy-dabrafenib. Hydroxy-dabrafenib undergoes further oxidation to carboxy-dabrafenib, which subsequently converts to desmethyl-dabrafenib via a pH-dependent decarboxylation. The half-lives for carboxy-and desmethyl-dabrafenib were longer than for parent and hydroxy-dabrafenib (18-20 vs. 5-6 hours). Based on area under the plasma concentration-time curve, dabrafenib, hydroxy-, carboxy-, and desmethyl-dabrafenib accounted for 11%, 8%, 54%, and 3% of the plasma radioactivity, respectively. These results demonstrate that the major route of elimination of dabrafenib is via oxidative metabolism (48% of the dose) and biliary excretion. Based on our understanding of the decarboxylation of carboxy-dabrafenib, a low pH-driven, nonenzymatic mechanism involving participation of the aryl nitrogen is proposed to allow prediction of metabolic oxidation and decarboxylation of drugs containing an aryl nitrogen positioned a to an alkyl (ethyl or t-butyl) side chain.

The Metabolic Drug-Drug Interaction Profile of Dabrafenib: In Vitro Investigations and Quantitative Extrapolation of the P450-Mediated DDI Risk

“…The mean percentage of the excreted dose in feces that represented oxidative metabolites was approximately 48%. Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine (Bershas et al, 2013). Therefore, P450-mediated oxidation likely contributes .70% to the metabolism of dabrafenib in vivo.…”

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

“…Dabrafenib is metabolized into its carboxy, hydroxyl, and desmethyl metabolites 81. The hydroxyl metabolite showed similar IC 50 values to dabrafenib in vitro .…”

Dabrafenib in combination with trametinib for the treatment of metastatic melanoma

“…In four patients receiving a dose of 95 mg of [(14)C]dabrafenib, 71% was recovered in the feces and 23% was excreted in the urine, with no detection of the parent drug in the urine. Dabrafenib is metabolized mainly by oxidation of the t-butyl group to form hydroxy-dabrafenib [14].…”