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Research ArticleArticle

Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites

Harma Ellens, Marta Johnson, Sarah K. Lawrence, Cory Watson, Liangfu Chen and Lauren E. Richards-Peterson
Drug Metabolism and Disposition June 2017, 45 (6) 646-656; DOI: https://doi.org/10.1124/dmd.116.073932
Harma Ellens
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania
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Marta Johnson
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania
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Sarah K. Lawrence
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania
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Cory Watson
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania
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Liangfu Chen
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania
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Lauren E. Richards-Peterson
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania
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Abstract

The BRAF inhibitor dabrafenib was recently approved for the treatment of certain BRAF V600 mutation-positive tumors, either alone or in combination therapy with the mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 inhibitor, trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction (DDI) risk assessment, which is currently an important part of drug development, regulatory submission, and drug registration. Dabrafenib and its major circulating metabolites (hydroxy-, carboxy-, and desmethyl-dabrafenib) were investigated as inhibitors of the clinically relevant transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, and OAT3. The DDI Guidance risk assessment decision criteria for inhibition of BCRP, OATP1B1 and OAT3 were slightly exceeded and therefore a minor DDI effect resulting from inhibition of these transporters remained possible. Biliary secretion is the major excretion pathway of dabrafenib-related material (71.1% of orally administered radiolabeled dose recovered in feces), whereas urinary excretion was observed as well (22.7% of the dose). In vitro uptake into human hepatocytes of the dabrafenib metabolites, but not of dabrafenib parent compound, was mediated, at least in part, by hepatic uptake transporters. The transporters responsible for uptake of the pharmacologically active hydroxy- and desmethyl dabrafenib could not be identified, whereas carboxy-dabrafenib was a substrate of several OATPs. Dabrafenib, hydroxy-, and desmethyl-dabrafenib were substrates of P-gp and BCRP, whereas carboxy-dabrafenib was not. Although a small increase in exposure to carboxy-dabrafenib upon inhibition of OATPs and an increase in exposure to desmethyl-dabrafenib upon inhibition of P-gp or BCRP cannot be excluded, the clinical significance of such increases is likely to be low.

Footnotes

    • Received August 18, 2016.
    • Accepted November 15, 2016.
  • This work was sponsored by GlaxoSmithKline Pharmaceuticals Inc. Dabrafenib is an asset of Novartis AG as of March 2, 2015.

  • https://doi.org/10.1124/dmd.116.073932.

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

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 45 (6)
Drug Metabolism and Disposition
Vol. 45, Issue 6
1 Jun 2017
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Research ArticleArticle

Risk for Transporter-Mediated Drug-Drug Interactions for Dabrafenib and Metabolites

Harma Ellens, Marta Johnson, Sarah K. Lawrence, Cory Watson, Liangfu Chen and Lauren E. Richards-Peterson
Drug Metabolism and Disposition June 1, 2017, 45 (6) 646-656; DOI: https://doi.org/10.1124/dmd.116.073932

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Research ArticleArticle

Risk for Transporter-Mediated Drug-Drug Interactions for Dabrafenib and Metabolites

Harma Ellens, Marta Johnson, Sarah K. Lawrence, Cory Watson, Liangfu Chen and Lauren E. Richards-Peterson
Drug Metabolism and Disposition June 1, 2017, 45 (6) 646-656; DOI: https://doi.org/10.1124/dmd.116.073932
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