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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) 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).
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fig02: 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).

Mentions: Following coadministration with rifampin under fasted condition, ibrutinib mean Cmax and AUClast decreased (Cmax: 42.1 ng/mL to 3.38 ng/mL; AUClast: 335 ng·h/mL to 38.0 ng·h/mL) compared with ibrutinib administration alone (Fig.2A). Intersubject variability for both Cmax and AUClast was greater than 60% following ibrutinib administration alone and greater than 70% following ibrutinib+rifampin. Median tmax was delayed from 1.76 to 3.00 h. Terminal t1/2 was similar; due to multiple data points below the quantification limit in the elimination phase, it could only be calculated for 5 of 17 participants.


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

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

fig02: 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).
Mentions: Following coadministration with rifampin under fasted condition, ibrutinib mean Cmax and AUClast decreased (Cmax: 42.1 ng/mL to 3.38 ng/mL; AUClast: 335 ng·h/mL to 38.0 ng·h/mL) compared with ibrutinib administration alone (Fig.2A). Intersubject variability for both Cmax and AUClast was greater than 60% following ibrutinib administration alone and greater than 70% following ibrutinib+rifampin. Median tmax was delayed from 1.76 to 3.00 h. Terminal t1/2 was similar; due to multiple data points below the quantification limit in the elimination phase, it could only be calculated for 5 of 17 participants.

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