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Research ArticleArticle

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

David A. Bershas, Daniele Ouellet, Donna B. Mamaril-Fishman, Noelia Nebot, Stanley W. Carson, Samuel C. Blackman, Royce A. Morrison, Jerry L. Adams, Kristen E. Jurusik, Dana M. Knecht, Peter D. Gorycki and Lauren E. Richards-Peterson
Drug Metabolism and Disposition December 2013, 41 (12) 2215-2224; DOI: https://doi.org/10.1124/dmd.113.053785
David A. Bershas
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Daniele Ouellet
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Donna B. Mamaril-Fishman
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Noelia Nebot
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Stanley W. Carson
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Samuel C. Blackman
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Royce A. Morrison
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Jerry L. Adams
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Kristen E. Jurusik
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Dana M. Knecht
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Peter D. Gorycki
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Lauren E. Richards-Peterson
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.A.B., D.B.M.-F., K.E.J., D.M.K., P.D.G., L.E.R.-P.); Department of Clinical Pharmacology Modeling and Simulation (D.O., N.N.) and Department of Oncology R&D (S.W.C.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania (S.C.B., J.L.A.); and Comprehensive Clinical Development NW, Tacoma, Washington (R.A.M)
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Abstract

A phase I study was conducted to assess the metabolism and excretion of [14C]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 µCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-high-performance 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 α to an alkyl (ethyl or t-butyl) side chain.

Footnotes

    • Received July 19, 2013.
    • Accepted October 4, 2013.
  • This work was supported by GlaxoSmithKline.

  • dx.doi.org/10.1124/dmd.113.053785.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (12)
Drug Metabolism and Disposition
Vol. 41, Issue 12
1 Dec 2013
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Research ArticleArticle

Dabrafenib Disposition in Cancer Patients

David A. Bershas, Daniele Ouellet, Donna B. Mamaril-Fishman, Noelia Nebot, Stanley W. Carson, Samuel C. Blackman, Royce A. Morrison, Jerry L. Adams, Kristen E. Jurusik, Dana M. Knecht, Peter D. Gorycki and Lauren E. Richards-Peterson
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2215-2224; DOI: https://doi.org/10.1124/dmd.113.053785

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Research ArticleArticle

Dabrafenib Disposition in Cancer Patients

David A. Bershas, Daniele Ouellet, Donna B. Mamaril-Fishman, Noelia Nebot, Stanley W. Carson, Samuel C. Blackman, Royce A. Morrison, Jerry L. Adams, Kristen E. Jurusik, Dana M. Knecht, Peter D. Gorycki and Lauren E. Richards-Peterson
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2215-2224; DOI: https://doi.org/10.1124/dmd.113.053785
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