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Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants.

de Jong J, Skee D, Murphy J, Sukbuntherng J, Hellemans P, Smit J, de Vries R, Jiao JJ, Snoeys J, Mannaert E - Pharmacol Res Perspect (2015)

Bottom Line: 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].All treatments were well-tolerated.

View Article: PubMed Central - PubMed

Affiliation: Janssen Research & Development San Diego, California.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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fig03: 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.

Mentions: Pretreatment with GFJ increased ibrutinib concentrations in plasma. DN_Cmax of ibrutinib increased by 3.5-fold, whereas DN_AUC increased by 2.2-fold in presence of single-strength GFJ compared with oral administration of 560 mg ibrutinib without GFJ under nonfasted condition (Fig.2C). On the other hand, the AUCs of ibrutinib following i.v. administration under nonfasted conditions with and without GFJ were the same. Mean Cmax was slightly higher with GFJ, but intrasubject variability was very high (84%) (Fig.3).


Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants.

de Jong J, Skee D, Murphy J, Sukbuntherng J, Hellemans P, Smit J, de Vries R, Jiao JJ, Snoeys J, Mannaert E - Pharmacol Res Perspect (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492731&req=5

fig03: 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.
Mentions: Pretreatment with GFJ increased ibrutinib concentrations in plasma. DN_Cmax of ibrutinib increased by 3.5-fold, whereas DN_AUC increased by 2.2-fold in presence of single-strength GFJ compared with oral administration of 560 mg ibrutinib without GFJ under nonfasted condition (Fig.2C). On the other hand, the AUCs of ibrutinib following i.v. administration under nonfasted conditions with and without GFJ were the same. Mean Cmax was slightly higher with GFJ, but intrasubject variability was very high (84%) (Fig.3).

Bottom Line: 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].All treatments were well-tolerated.

View Article: PubMed Central - PubMed

Affiliation: Janssen Research & Development San Diego, California.

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.

No MeSH data available.


Related in: MedlinePlus