当前位置： SCI文献检索 > EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY期刊下所有文献 > Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects.

Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects.

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 ng•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).

journal_name

Eur J Clin Pharmacol

journal_title

European journal of clinical pharmacology

authors

Hsyu PH,Pignataro DS,Matschke K

doi

10.1007/s00228-016-2108-z

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

49-56

issue

eissn

0031-6970

issn

1432-1041

pii

10.1007/s00228-016-2108-z

journal_volume

pub_type

杂志文章,随机对照试验

在线工具

Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects.