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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

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.
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fig01: 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.

Mentions: Following coadministration of ibrutinib with ketoconazole under fasted condition, mean DN_Cmax (dose normalized to 120 mg) of ibrutinib increased from 11.8 to 325 ng/mL and mean DN_AUClast increased from 71.4 to 1599 ng·h/mL (Fig.1A). Although dose proportionality was not formally tested for ibrutinib, no deviations from linearity were observed neither in the Phase I escalating dose study nor population PK study (imbruvica™ 2014; Marostica et al. 2015), thus justifying the dose-normalization of ibrutinib exposure in this study. Intersubject variability in ibrutinib+ketoconazole treated participants for both Cmax and AUClast were >50% following ibrutinib administration alone and approximately 40% when coadministered with ketoconazole. The Vd/F and CL/F were both lower following ibrutinib + ketoconazole compared with ibrutinib alone (Vd/F: 885 L vs. 19049 L; CL/F: 92.0 L/h vs. 2014 L/h, whereas there was no change in mean tmax (2.00 h vs. 1.75 h) and t1/2 (6.32 h vs. 8.20 h) (Table S1).


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)

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

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

fig01: 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.
Mentions: Following coadministration of ibrutinib with ketoconazole under fasted condition, mean DN_Cmax (dose normalized to 120 mg) of ibrutinib increased from 11.8 to 325 ng/mL and mean DN_AUClast increased from 71.4 to 1599 ng·h/mL (Fig.1A). Although dose proportionality was not formally tested for ibrutinib, no deviations from linearity were observed neither in the Phase I escalating dose study nor population PK study (imbruvica™ 2014; Marostica et al. 2015), thus justifying the dose-normalization of ibrutinib exposure in this study. Intersubject variability in ibrutinib+ketoconazole treated participants for both Cmax and AUClast were >50% following ibrutinib administration alone and approximately 40% when coadministered with ketoconazole. The Vd/F and CL/F were both lower following ibrutinib + ketoconazole compared with ibrutinib alone (Vd/F: 885 L vs. 19049 L; CL/F: 92.0 L/h vs. 2014 L/h, whereas there was no change in mean tmax (2.00 h vs. 1.75 h) and t1/2 (6.32 h vs. 8.20 h) (Table S1).

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