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.
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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