Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects.
Eur J Clin Pharmacol
; 73(1): 49-56, 2017 Jan.
Article
in En
| MEDLINE
| ID: mdl-27718000
ABSTRACT
PURPOSE:
Bosutinib is an oral, dual Src and Abl tyrosine kinase inhibitor (TKI) approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia resistant or intolerant to prior TKI therapy. Bosutinib is primarily metabolized by cytochrome P450 (CYP) 3A4, suggesting drug interaction potential with other CYP3A4 modulators. This open-label, randomized, 2-sequence, 2-period crossover study assessed the effect of single-dose aprepitant, a moderate CYP3A4 inhibitor, on the single-dose pharmacokinetic profile of oral bosutinib 500 mg.METHODS:
Nineteen healthy, fed adults received bosutinib (100 mg × 5) alone or coadministered with aprepitant (125 mg × 1) in each treatment period (with a ≥14-day washout); serial blood samples were analyzed. Safety was evaluated.RESULTS:
Following coadministration of aprepitant with bosutinib, the area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) and maximum plasma concentration (C max) were higher than in bosutinib alone (AUCinf, 4719 and 2268 ngâ¢h/mL; C max, 146.0 and 94.94 ng/mL). For bosutinib with aprepitant versus bosutinib alone, mean terminal elimination half-life was similar (25.99 vs 27.79 h), time to C max was longer (6.02 vs 4.15 h), and apparent oral clearance (CL/F) was decreased (105.9 vs 220.4 L/h). The ratio of adjusted geometric means of AUCinf and C max for bosutinib with aprepitant relative to bosutinib alone were 199 % (90 % confidence interval, 167-237 %) and 153 % (127-184 %), respectively. Both treatments were well tolerated.CONCLUSION:
In healthy volunteers, administering a single dose of aprepitant increased the AUC and C max following a single dose of bosutinib by 99 and 53 %, respectively. These results are consistent with a moderate CYP3A4 inhibitor effect of aprepitant on bosutinib (Trial Registration ClinicalTrials.gov NCT02058277).Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Quinolines
/
Morpholines
/
Protein Kinase Inhibitors
/
Cytochrome P-450 CYP3A Inhibitors
/
Aniline Compounds
/
Antiemetics
/
Antineoplastic Agents
/
Nitriles
Type of study:
Clinical_trials
/
Prognostic_studies
Limits:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Eur J Clin Pharmacol
Year:
2017
Document type:
Article
Affiliation country:
United States