Effect of bosutinib on the absorption of dabigatran etexilate mesylate, a P-glycoprotein substrate, in healthy subjects.
Purpose: Bosutinib, a dual Src and Abl tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, demonstrated concentration-dependent inhibitory effects on P-glycoprotein (P-gp)-mediated digoxin efflux in vitro, suggesting that bosutinib may inhibit P-gp substrates. The effect of bosu...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 73; no. 1; pp. 57 - 64 |
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| Autores principales: | , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Springer Nature
Jan2017
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=120506394&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 120506394 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: 120506394 120506394 143953222 120506394 10.1007/s00228-016-2115-0 120506394 ppf: 57 ppct: 7 formats: fmt: @attributes: type: P tig: atl: Effect of bosutinib on the absorption of dabigatran etexilate mesylate, a P-glycoprotein substrate, 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: Dabigatran Etexilate Tyrosine Kinase Inhibitors Pharmacokinetics Evaluation Human Drug Interactions Absorption In Vitro Studies ab: Purpose: Bosutinib, a dual Src and Abl tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, demonstrated concentration-dependent inhibitory effects on P-glycoprotein (P-gp)-mediated digoxin efflux in vitro, suggesting that bosutinib may inhibit P-gp substrates. The effect of bosutinib on dabigatran etexilate mesylate (EM) absorption, a P-gp substrate, was evaluated. Methods: In this open-label, randomized, single-dose, one-cohort, two-sequence, two-period crossover study, healthy, fed subjects received dabigatran EM (150 mg × 1 orally) alone or 1 h after receiving bosutinib tablets (100 mg × 5 orally). Results: Dabigatran EM monotherapy and concurrent administration of dabigatran EM with bosutinib resulted in similar values for concentration time curves from time zero extrapolated to infinity (AUC), but slightly lower maximum plasma concentration ( C ) values (AUC, 1182 and 1186 ng·h/mL, respectively; C , 129.8 and 114.1 ng/mL). The time to maximum concentration for dabigatran was 2.99 and 3.99 h for combination therapy. The ratio of the adjusted geometric means (test/reference) of dabigatran AUC and C (90 % confidence interval) were 101.4 % (89.6-114.9 %) and 89.7 % (77.8-103.4 %), respectively, following administration of dabigatran EM with bosutinib (test) relative to dabigatran EM administered alone (reference). Six subjects receiving combination treatment reported a total of seven adverse events (AEs) versus none for subjects receiving monotherapy alone. All AEs were mild to moderate and considered treatment related. Conclusion: These data demonstrate that single doses of bosutinib do not affect dabigatran exposure, suggesting that bosutinib is not a clinical inhibitor of P-gp. Trial registration: ClinicalTrials.gov NCT02102633. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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