Open AccessEffect of CYP 3A perpetrators on ibrutinib exposure in healthy participants
Author(s) -
Jong Jan,
Skee Donna,
Murphy Joe,
Sukbuntherng Juthamas,
Hellemans Peter,
Smit Johan,
Vries Ronald,
Jiao Juhui James,
Snoeys Jan,
Mannaert Erik
Publication year - 2015
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.156
Subject(s) - ibrutinib , pharmacology , psychology , medicine , clinical psychology , leukemia , chronic lymphocytic leukemia
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 CYP 3A in ibrutinib metabolism, effect of coadministration of CYP 3A 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 CYP 3A inhibitors [Study 1: 40 mg; Study 3: 140 mg], as safety precaution. Under fasted condition, ketoconazole increased ibrutinib dose‐normalized ( DN ) exposure [DN‐AUC last : 24‐fold; DN‐ C max : 29‐fold], rifampin decreased ibrutinib exposure [ C max : 13‐fold; AUC last : 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 CYP 3A. Half‐life was not affected by CYP perpetrators indicating the interaction was mainly on first‐pass extraction. All treatments were well‐tolerated.