The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of 14 C-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 (C max ) 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 C max 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 AUC 0-24 h and AUC 0-72 h , respectively. No effect of CYP2D6 genotype was observed on ibrutinib metabolism. Ibrutinib was well-tolerated by healthy participants.

Ronald de Vries graduated in Organic and Analytical Chemistry at the Free University of Amsterdam, The Netherlands. After working in a Contract Laboratory (CRO) for 7 years, he joined Janssen R&D in 1998. At Janssen R&D, Belgium, Ronald worked in the bioanalytical department that supports both clinical and nonclinical bioanalysis. In this department he had several roles, such as providing the bioanalytical support for various drug development programs and leading the method establishment group. He has done numerous global assay transfers to/from Janssen from/to other laboratories and plays an important role in the introduction and application of new technologies and applied innovation in the department. In 2014 he started in the drug metabolism and pharmacokinetics department of Janssen R&D, where his main tasks are in vivo and in vitro metabolite identification using high resolution MS and Radiodetection.

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