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. 2015 Aug;3(4):e00156.
doi: 10.1002/prp2.156. Epub 2015 Jun 24.

Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants

Jan de Jong  1 , Donna Skee  2 , Joe Murphy  2 , Juthamas Sukbuntherng  3 , Peter Hellemans  4 , Johan Smit  4 , Ronald de Vries  4 , Juhui James Jiao  2 , Jan Snoeys  4 , Erik Mannaert  4
Affiliations

Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants

Jan de Jong et al. Pharmacol Res Perspect. 2015 Aug.

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.

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Figures

Figure 1
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
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
Figure 3
Mean (SD) AUClast and Cmax 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
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).
See this image and copyright information in PMC

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