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Research ArticleAccelerated Communication

Use of Transgenic Mouse Models to Understand the Oral Disposition and Drug-Drug Interaction Potential of Cobimetinib, a MEK Inhibitor

Edna F. Choo, Sarah Woolsey, Kevin DeMent, Justin Ly, Kirsten Messick, Ann Qin and Ryan Takahashi
Drug Metabolism and Disposition June 2015, 43 (6) 864-869; DOI: https://doi.org/10.1124/dmd.115.063743
Edna F. Choo
Genentech Inc., South San Francisco, California
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Sarah Woolsey
Genentech Inc., South San Francisco, California
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Kevin DeMent
Genentech Inc., South San Francisco, California
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Justin Ly
Genentech Inc., South San Francisco, California
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Kirsten Messick
Genentech Inc., South San Francisco, California
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Ann Qin
Genentech Inc., South San Francisco, California
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Ryan Takahashi
Genentech Inc., South San Francisco, California
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Abstract

Data from the clinical absolute bioavailability (F) study with cobimetinib suggested that F was lower than predicted based on its low hepatic extraction and good absorption. The CYP3A4 transgenic (Tg) mouse model with differential expression of CYP3A4 in the liver (Cyp3a−/−Tg-3A4Hep) or intestine (Cyp3a−/−Tg-3A4Int) and both liver and intestine (Cyp3a−/−Tg-3A4Hep/Int) were used to study the contribution of intestinal metabolism to the F of cobimetinib. In addition, the effect of CYP3A4 inhibition and induction on cobimetinib exposures was tested in the Cyp3a−/−Tg-3A4Hep/Int and PXR-CAR-CYP3A4/CYP3A7 mouse models, respectively. After i.v. administration of 1 mg/kg cobimetinib to wild-type [(WT) FVB], Cyp3a−/−Tg-3A4Hep, Cyp3a−/−Tg-3A4Int, or Cyp3a−/−Tg-3A4Hep/Int mice, clearance (CL) (26-35 ml/min/kg) was similar in the CYP3A4 transgenic and WT mice. After oral administration of 5 mg/kg cobimetinib, the area under the curve (AUC) values of cobimetinib in WT, Cyp3a−/−Tg-3A4Hep, Cyp3a−/−Tg-3A4Int, or Cyp3a−/−Tg-3A4Hep/Int mice were 1.35, 3.39, 1.04, and 0.701 μM⋅h, respectively. The approximately 80% lower AUC of cobimetinib in transgenic mice when intestinal CYP3A4 was present suggested that the intestinal first pass contributed to the oral CL of cobimetinib. Oxidative metabolites observed in human circulation were also observed in the transgenic mice. In drug-drug interaction (DDI) studies using Cyp3a−/−Tg-3A4Hep/Int mice, 8- and 4-fold increases in oral and i.v. cobimetinib exposure, respectively, were observed with itraconazole co-administration. In PXR-CAR-CYP3A4/CYP3A7 mice, rifampin induction decreased cobimetinib oral exposure by approximately 80%. Collectively, these data support the conclusion that CYP3A4 intestinal metabolism contributes to the oral disposition of cobimetinib and suggest that under certain circumstances the transgenic model may be useful in predicting clinical DDIs.

Footnotes

    • Received February 8, 2015.
    • Accepted March 26, 2015.
  • dx.doi.org/10.1124/dmd.115.063743.

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

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (6)
Drug Metabolism and Disposition
Vol. 43, Issue 6
1 Jun 2015
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Research ArticleAccelerated Communication

Use of CYP Transgenic Mouse Models

Edna F. Choo, Sarah Woolsey, Kevin DeMent, Justin Ly, Kirsten Messick, Ann Qin and Ryan Takahashi
Drug Metabolism and Disposition June 1, 2015, 43 (6) 864-869; DOI: https://doi.org/10.1124/dmd.115.063743

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Research ArticleAccelerated Communication

Use of CYP Transgenic Mouse Models

Edna F. Choo, Sarah Woolsey, Kevin DeMent, Justin Ly, Kirsten Messick, Ann Qin and Ryan Takahashi
Drug Metabolism and Disposition June 1, 2015, 43 (6) 864-869; DOI: https://doi.org/10.1124/dmd.115.063743
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