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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

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).
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fig04: 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).

Mentions: The magnitude of observed DDI was higher with higher baseline clearance. The higher the baseline CL/F, the larger the effect of ketoconazole. This trend was not observed clearly for the weaker (and intestine-specific) inhibitor GFJ, or for the inducer rifampin (Fig.4).


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)

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

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

fig04: 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).
Mentions: The magnitude of observed DDI was higher with higher baseline clearance. The higher the baseline CL/F, the larger the effect of ketoconazole. This trend was not observed clearly for the weaker (and intestine-specific) inhibitor GFJ, or for the inducer rifampin (Fig.4).

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