title: Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants.
abstract: Ibrutinib (PCI-32765), a potent covalent inhibitor of Bruton's tyrosine kinase, has shown efficacy against a variety of B-cell malignancies. Given the prominent role of CYP3A in ibrutinib metabolism, effect of coadministration of CYP3A perpetrators with ibrutinib was evaluated in healthy adults. Ibrutinib (120 mg [Study 1, fasted], 560 mg [studies 2 (fasted), and 3 (nonfasted)]) was given alone and with ketoconazole [Study 1; 400 mg q.d.], rifampin [Study 2; 600 mg q.d.], and grapefruit juice [GFJ, Study 3]. Lower doses of ibrutinib were used together with CYP3A inhibitors [Study 1: 40 mg; Study 3: 140 mg], as safety precaution. Under fasted condition, ketoconazole increased ibrutinib dose-normalized (DN) exposure [DN-AUClast: 24-fold; DN-C max: 29-fold], rifampin decreased ibrutinib exposure [C max: 13-fold; AUClast: 10-fold]. Under nonfasted condition, GFJ caused a moderate increase [DN-C max: 3.5-fold; DN-AUC: 2.2-fold], most likely through inhibition of intestinal CYP3A. Half-life was not affected by CYP perpetrators indicating the interaction was mainly on first-pass extraction. All treatments were well-tolerated.
authors.affiliation: Janssen Research & Development San Diego, California.
authors.forename: Jan
authors.initials: J
authors.lastname: de Jong
authors.affiliation: Janssen Research & Development Raritan, New Jersey.
authors.forename: Donna
authors.initials: D
authors.lastname: Skee
authors.affiliation: Janssen Research & Development Raritan, New Jersey.
authors.forename: Joe
authors.initials: J
authors.lastname: Murphy
authors.affiliation: Pharmacyclics Inc. Sunnyvale, California.
authors.forename: Juthamas
authors.initials: J
authors.lastname: Sukbuntherng
authors.affiliation: Janssen Research & Development Beerse, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Hellemans
authors.affiliation: Janssen Research & Development Beerse, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Smit
authors.affiliation: Janssen Research & Development Beerse, Belgium.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Vries
authors.affiliation: Janssen Research & Development Raritan, New Jersey.
authors.forename: Juhui James
authors.initials: JJ
authors.lastname: Jiao
authors.affiliation: Janssen Research & Development Beerse, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Janssen Research & Development Beerse, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Mannaert
keywords: Bioavailability; CYP3A perpetrators; grapefruit juice; ibrutinib; ketoconazole; rifampin