Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects.
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 inter...
| Published in: | European Journal of Clinical Pharmacology Vol. 73; no. 1; pp. 49 - 57 |
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| Main Authors: | , , |
| Format: | research tables/charts Journal Article |
| Published: |
Springer Nature
Jan2017
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=120506380&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 120506380 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Jan2017 vid: 73 iid: 1 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 120506380 120506380 144176701 120506380 10.1007/s00228-016-2108-z 120506380 ppf: 49 ppct: 8 formats: fmt: @attributes: type: P tig: atl: Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects. aug: au: Hsyu, Poe-Hirr Pignataro, Daniela Matschke, Kyle affil: Pfizer Inc , 10646 Science Center Drive La Jolla 92121 USA sug: subj: Tyrosine Kinase Inhibitors Leukemia, Myeloid Drug Therapy Pharmacokinetics Evaluation Human Adult Male Female Drug Interactions Cytochrome P-450 Enzyme System Adult: 19-44 years Male Female ab: 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 (AUC) and maximum plasma concentration ( C ) were higher than in bosutinib alone (AUC, 4719 and 2268 ng•h/mL; C , 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 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 AUC and C 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 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: NCT02058277). pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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