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Research ArticleArticle

Absorption, Metabolism, and Excretion of Oral 14C Radiolabeled Ibrutinib: An Open-Label, Phase I, Single-Dose Study in Healthy Men

Ellen Scheers, Laurent Leclercq, Jan de Jong, Nini Bode, Marc Bockx, Aline Laenen, Filip Cuyckens, Donna Skee, Joe Murphy, Juthamas Sukbuntherng and Geert Mannens
Drug Metabolism and Disposition February 2015, 43 (2) 289-297; DOI: https://doi.org/10.1124/dmd.114.060061
Ellen Scheers
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Laurent Leclercq
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Jan de Jong
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Nini Bode
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Marc Bockx
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Aline Laenen
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Filip Cuyckens
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Donna Skee
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Joe Murphy
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Juthamas Sukbuntherng
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Geert Mannens
Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Beerse, Belgium (E.S., L.L., M.B., A.L., F.C., G.M.); Clinical Pharmacology, Janssen R&D, San Diego, California (J.d.J.); Pre-Clinical Project Development, Janssen R&D, Beerse, Belgium (N.B.); Clinical Pharmacology, Janssen R&D, Raritan, New Jersey (D.S., J.M.); and Pharmacyclics, Sunnyvale, California (J.S.)
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Abstract

The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of 14C-labeled ibrutinib. The mean (S.D.) cumulative excretion of radioactivity of the dose was 7.8% (1.4%) in urine and 80.6% (3.1%) in feces with <1% excreted as parent ibrutinib. Only oxidative metabolites and very limited parent compound were detected in feces, and this indicated that ibrutinib was completely absorbed from the gastrointestinal tract. Metabolism occurred via three major pathways (hydroxylation of the phenyl (M35), opening of the piperidine (M25 and M34), and epoxidation of the ethylene on the acryloyl moiety with further hydrolysis to dihydrodiol (PCI-45227, and M37). Additional metabolites were formed by combinations of the primary metabolic pathways or by further metabolism. In blood and plasma, a rapid initial decline in radioactivity was observed along with long terminal elimination half-life for total radioactivity. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) for total radioactivity were higher in plasma compared with blood. The main circulating entities in blood and plasma were M21 (sulfate conjugate of a monooxidized metabolite on phenoxyphenyl), M25, M34, M37 (PCI-45227), and ibrutinib. At Cmax of radioactivity, 12% of total radioactivity was accounted for by covalent binding in human plasma. More than 50% of total plasma radioactivity was attributed to covalently bound material from 8 hours onward; as a result, covalent binding accounted for 38% and 51% of total radioactivity AUC0–24 h and AUC0–72 h, respectively. No effect of CYP2D6 genotype was observed on ibrutinib metabolism. Ibrutinib was well-tolerated by healthy participants.

Footnotes

    • Received July 22, 2014.
    • Accepted December 4, 2014.
  • This study was supported by funding from Janssen Research & Development, LLC. This study is registered at ClinicalTrials.gov [NCT01674322].

  • All authors met International Committee of Medical Journal Editors (ICMJE) criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data and made the final decision about where to present these data. G.M., L.L., N.B., F.C., E.S., A.L., M.B., J.d.J., D.S., and J.M. are employees of Janssen R&D. The Janssen companies are Johnson & Johnson companies. G.M., L.L., N.B., F.C., J.d.J., and J.M. hold stocks in Johnson & Johnson. J.S. is an employee of and holds stocks in Pharmacyclics.

  • dx.doi.org/10.1124/dmd.114.060061.

  • ↵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: 43 (2)
Drug Metabolism and Disposition
Vol. 43, Issue 2
1 Feb 2015
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Research ArticleArticle

Absorption, Metabolism, and Excretion of Ibrutinib

Ellen Scheers, Laurent Leclercq, Jan de Jong, Nini Bode, Marc Bockx, Aline Laenen, Filip Cuyckens, Donna Skee, Joe Murphy, Juthamas Sukbuntherng and Geert Mannens
Drug Metabolism and Disposition February 1, 2015, 43 (2) 289-297; DOI: https://doi.org/10.1124/dmd.114.060061

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Research ArticleArticle

Absorption, Metabolism, and Excretion of Ibrutinib

Ellen Scheers, Laurent Leclercq, Jan de Jong, Nini Bode, Marc Bockx, Aline Laenen, Filip Cuyckens, Donna Skee, Joe Murphy, Juthamas Sukbuntherng and Geert Mannens
Drug Metabolism and Disposition February 1, 2015, 43 (2) 289-297; DOI: https://doi.org/10.1124/dmd.114.060061
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