Absorption, metabolism, and excretion of oral ¹⁴C radiolabeled ibrutinib: an open-label, phase I, single-dose study in healthy men

Drug Metab Dispos. 2015 Feb;43(2):289-97. doi: 10.1124/dmd.114.060061. Epub 2014 Dec 8.


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.

Trial registration: ClinicalTrials.gov NCT01674322.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / analysis
  • Adenine / blood
  • Adenine / urine
  • Administration, Oral
  • Adult
  • Agammaglobulinaemia Tyrosine Kinase
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / analysis
  • Antineoplastic Agents / pharmacokinetics*
  • Biotransformation
  • Carbon Radioisotopes
  • Feces / chemistry
  • Half-Life
  • Humans
  • Hydrolysis
  • Hydroxylation
  • Intestinal Absorption*
  • Intestinal Elimination
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Oxidation-Reduction
  • Piperidines
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / analysis
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrazoles / administration & dosage
  • Pyrazoles / adverse effects
  • Pyrazoles / analysis
  • Pyrazoles / blood
  • Pyrazoles / pharmacokinetics*
  • Pyrazoles / urine
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects
  • Pyrimidines / analysis
  • Pyrimidines / pharmacokinetics*
  • Renal Elimination


  • Antineoplastic Agents
  • Carbon Radioisotopes
  • PCI-45227
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • ibrutinib
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • Adenine

Associated data

  • ClinicalTrials.gov/NCT01674322