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Research ArticleArticle

Pharmacokinetics, Metabolism, and Excretion of [14C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans

Bill J. Smith, Yazdi Pithavala, Hai-Zhi Bu, Ping Kang, Brian Hee, Alan J. Deese, William F. Pool, Karen J. Klamerus, Ellen Y. Wu and Deepak K. Dalvie
Drug Metabolism and Disposition May 2014, 42 (5) 918-931; DOI: https://doi.org/10.1124/dmd.113.056531
Bill J. Smith
Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA
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Yazdi Pithavala
Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA
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Hai-Zhi Bu
Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA
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Ping Kang
Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA
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Brian Hee
Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA
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Alan J. Deese
Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA
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William F. Pool
Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA
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Karen J. Klamerus
Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA
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Ellen Y. Wu
Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA
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Deepak K. Dalvie
Pharmacokinetics, Dynamics and Metabolism (B.J.S., H.-Z.B., P.K., W.F.P., E.Y.W., D.K.D.), Pfizer Oncology-Clinical Pharmacology (Y.P., B.H., K.J.K.), and Pharmaceutical Sciences (A.J.D.), Pfizer Inc., Worldwide Research and Development, La Jolla Laboratories, San Diego, CA
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Abstract

The disposition of a single oral dose of 5 mg (100 μCi) of [14C]axitinib was investigated in fasted healthy human subjects (N = 8). Axitinib was rapidly absorbed, with a median plasma Tmax of 2.2 hours and a geometric mean Cmax and half-life of 29.2 ng/ml and 10.6 hours, respectively. The plasma total radioactivity-time profile was similar to that of axitinib but the AUC was greater, suggesting the presence of metabolites. The major metabolites in human plasma (0–12 hours), identified as axitinib N-glucuronide (M7) and axitinib sulfoxide (M12), were pharmacologically inactive, and with axitinib comprised 50.4%, 16.2%, and 22.5% of the radioactivity, respectively. In excreta, the majority of radioactivity was recovered in most subjects by 48 hours postdose. The median radioactivity excreted in urine, feces, and total recovery was 22.7%, 37.0%, and 59.7%, respectively. The recovery from feces was variable across subjects (range, 2.5%–60.2%). The metabolites identified in urine were M5 (carboxylic acid), M12 (sulfoxide), M7 (N-glucuronide), M9 (sulfoxide/N-oxide), and M8a (methylhydroxy glucuronide), accounting for 5.7%, 3.5%, 2.6%, 1.7%, and 1.3% of the dose, respectively. The drug-related products identified in feces were unchanged axitinib, M14/15 (mono-oxidation/sulfone), M12a (epoxide), and an unidentified metabolite, comprising 12%, 5.7%, 5.1%, and 5.0% of the dose, respectively. The proposed mechanism to form M5 involved a carbon-carbon bond cleavage via M12a, followed by rearrangement to a ketone intermediate and subsequent Baeyer-Villiger rearrangement, possibly through a peroxide intermediate. In summary, the study characterized axitinib metabolites in circulation and primary elimination pathways of the drug, which were mainly oxidative in nature.

Footnotes

    • Received December 16, 2013.
    • Accepted March 7, 2014.
  • ↵1 Current affiliation: 3D BioOptima Co., Ltd., Suzhou, China.

  • ↵2 Current affiliation: Vertex Pharmaceuticals Inc., San Diego, California.

  • ↵3 Current affiliation: Genentech, South San Francisco, California.

  • This study was sponsored by Pfizer Inc.

  • dx.doi.org/10.1124/dmd.113.056531.

  • ↵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 (5)
Drug Metabolism and Disposition
Vol. 42, Issue 5
1 May 2014
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Research ArticleArticle

Axitinib Human Metabolism

Bill J. Smith, Yazdi Pithavala, Hai-Zhi Bu, Ping Kang, Brian Hee, Alan J. Deese, William F. Pool, Karen J. Klamerus, Ellen Y. Wu and Deepak K. Dalvie
Drug Metabolism and Disposition May 1, 2014, 42 (5) 918-931; DOI: https://doi.org/10.1124/dmd.113.056531

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Research ArticleArticle

Axitinib Human Metabolism

Bill J. Smith, Yazdi Pithavala, Hai-Zhi Bu, Ping Kang, Brian Hee, Alan J. Deese, William F. Pool, Karen J. Klamerus, Ellen Y. Wu and Deepak K. Dalvie
Drug Metabolism and Disposition May 1, 2014, 42 (5) 918-931; DOI: https://doi.org/10.1124/dmd.113.056531
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