title: Absorption, metabolism, and excretion of oral ¹⁴C radiolabeled ibrutinib: an open-label, phase I, single-dose study in healthy men.
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 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.
authors.affiliation: 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.).
authors.forename: Ellen
authors.initials: E
authors.lastname: Scheers
authors.affiliation: 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.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Leclercq
authors.affiliation: 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.).
authors.forename: Jan
authors.initials: J
authors.lastname: de Jong
authors.affiliation: 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.).
authors.forename: Nini
authors.initials: N
authors.lastname: Bode
authors.affiliation: 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.).
authors.forename: Marc
authors.initials: M
authors.lastname: Bockx
authors.affiliation: 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.).
authors.forename: Aline
authors.initials: A
authors.lastname: Laenen
authors.affiliation: 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.).
authors.forename: Filip
authors.initials: F
authors.lastname: Cuyckens
authors.affiliation: 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.).
authors.forename: Donna
authors.initials: D
authors.lastname: Skee
authors.affiliation: 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.).
authors.forename: Joe
authors.initials: J
authors.lastname: Murphy
authors.affiliation: 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.).
authors.forename: Juthamas
authors.initials: J
authors.lastname: Sukbuntherng
authors.affiliation: 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.) gmannens@its.jnj.com.
authors.forename: Geert
authors.initials: G
authors.lastname: Mannens
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000032:analysis / Q000097:blood / Q000652:urine; D000284:Administration, Oral; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D001711:Biotransformation; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D006900:Hydroxylation; D007408:Intestinal Absorption; D066237:Intestinal Elimination; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010084:Oxidation-Reduction; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D065667:Renal Elimination
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; C000602566:PCI-45227; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine