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Research ArticleArticle

Cynomolgus Monkey as a Surrogate for Human Aldehyde Oxidase Metabolism of the EGFR Inhibitor BIBX1382

J. Matthew Hutzler, Matthew A. Cerny, Young-Sun Yang, Constance Asher, Diane Wong, Kosea Frederick and Kyle Gilpin
Drug Metabolism and Disposition October 2014, 42 (10) 1751-1760; DOI: https://doi.org/10.1124/dmd.114.059030
J. Matthew Hutzler
Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut
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Matthew A. Cerny
Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut
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Young-Sun Yang
Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut
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Constance Asher
Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut
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Diane Wong
Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut
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Kosea Frederick
Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut
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Kyle Gilpin
Boehringer-Ingelheim Pharmaceuticals Inc., Medicinal Chemistry, Drug Discovery Support (DMPK), Ridgefield, Connecticut
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Abstract

BIBX1382 was an epidermal growth factor receptor inhibitor under clinical investigation for treatment of cancer. This candidate possessed an attractive preclinical absorption, distribution, metabolism, and excretion profile, yet failed in clinical studies due in part to poor oral exposure, resulting from extensive metabolism by aldehyde oxidase (AO). In vitro metabolism studies were performed in liver cytosol and cryopreserved hepatocytes from multiple species. In addition, a pharmacokinetic study was performed in cynomolgus monkey for comparison with the reported human pharmacokinetics of BIBX1382. Estimated hepatic clearance of BIBX1382 in rhesus (42 ml/min per kg) and cynomolgus monkey (43 ml/min per kg) liver cytosol was comparable to human (≥93% of liver blood flow). Metabolite identification after incubation of BIBX1382 in liver cytosol fortified with the AO inhibitor raloxifene confirmed that AO is involved in the formation of the predominant metabolite (BIBU1476, M1) in cynomolgus monkey. After intravenous and oral administration of BIBX1382 to cynomolgus monkeys, high plasma clearance (118 ml/min per kg) and low oral exposure (Cmax = 12.7 nM and 6% oral bioavailability) was observed, with the exposure of M1 exceeding BIBX1382 after oral dosing. This pharmacokinetic profile compared favorably with the human clinical data of BIBX1382 (plasma clearance 25–55 ml/min per kg and 5% oral bioavailability). Thus, it appears that cynomolgus monkey represents a suitable surrogate for the observed human AO metabolism of BIBX1382. To circumvent clinical failures due to uncharacterized metabolism by AO, in vitro studies in the appropriate subcellular fraction, followed by pharmacokinetic and toxicokinetic studies in the appropriately characterized surrogate species should be conducted for substrates of AO.

Footnotes

    • Received May 13, 2014.
    • Accepted July 17, 2014.
  • dx.doi.org/10.1124/dmd.114.059030

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

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (10)
Drug Metabolism and Disposition
Vol. 42, Issue 10
1 Oct 2014
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Research ArticleArticle

BIBX1382 Metabolism in Human and Cynomolgus Monkey

J. Matthew Hutzler, Matthew A. Cerny, Young-Sun Yang, Constance Asher, Diane Wong, Kosea Frederick and Kyle Gilpin
Drug Metabolism and Disposition October 1, 2014, 42 (10) 1751-1760; DOI: https://doi.org/10.1124/dmd.114.059030

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Research ArticleArticle

BIBX1382 Metabolism in Human and Cynomolgus Monkey

J. Matthew Hutzler, Matthew A. Cerny, Young-Sun Yang, Constance Asher, Diane Wong, Kosea Frederick and Kyle Gilpin
Drug Metabolism and Disposition October 1, 2014, 42 (10) 1751-1760; DOI: https://doi.org/10.1124/dmd.114.059030
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