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.

Keywords: Bioavailability; CYP3A perpetrators; grapefruit juice; ibrutinib; ketoconazole; rifampin.

Figure 1

Dose-normalized mean (SD) logarithmic-linear plasma concentration-time profiles following oral administration of ibrutinib (120 mg) alone (day 1) and in combination with ketoconazole (40 mg Ibrutinib+400 mg Ketoconazole) (day 7) to healthy men. (A) Ibrutinib; (B) PCI-45227.

Figure 2

Mean (SD) logarithmic-linear plasma concentration-time profiles of ibrutinib (560 mg) and metabolite PCI-45227 in absence and presence of CYP perpetrators: Rifampin (600 mg) (A and B: fasted condition) Grapefruit Juice (C and D: nonfasted condition).

Figure 3

Mean (SD) AUC_last and C_max of ibrutinib following oral administration of ibrutinib alone and in combination with ketoconazole, rifampin, or grapefruit juice; data dose normalized to 560 mg.

Figure 4

Fold-change in AUC versus baseline apparent clearance following oral administration of ibrutinib with ketoconazole or rifampin (both under fasted conditions) or with grapefruit juice (with standard meal).