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Effect of bosutinib on the absorption of dabigatran etexilate mesylate, a P-glycoprotein substrate, in healthy subjects

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

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 (AUCinf), but slightly lower maximum plasma concentration (C max) values (AUCinf, 1182 and 1186 ng·h/mL, respectively; C max, 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 AUCinf and C max (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. https://clinicaltrials.gov/ct2/show/NCT02102633?term=NCT02102633&rank=1

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Acknowledgments

This study was sponsored by Pfizer Inc. Medical writing support was provided by Simon Slater, PhD, of Complete Healthcare Communications, LLC, and was funded by Pfizer Inc.

Contributions of authors

PH conceived and designed the study; PH provided the study material or patients; DSP, PH, KM analyzed and interpreted the data; PH and KM wrote the manuscript; and all the authors approved the final manuscript.

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Authors and Affiliations

  1. Pfizer Inc, 10646 Science Center Drive, La Jolla, CA, 92121, USA

    Poe-Hirr Hsyu

  2. Pfizer Inc, Walton Oaks, Dorking Road, Surrey, KT20 7NS, UK

    Daniela Soriano Pignataro

  3. Pfizer Inc, 500 Arcola Road, Collegeville, PA, 19426, USA

    Kyle Matschke

Authors
  1. Poe-Hirr Hsyu
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  2. Daniela Soriano Pignataro
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  3. Kyle Matschke
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Corresponding author

Correspondence to Poe-Hirr Hsyu.

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Ethical approval

The protocol was approved by an independent ethics committee and was conducted in compliance with the ethical principles from the Declaration of Helsinki and with all International Conference on Harmonisation Good Clinical Practice Guidelines.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Disclosures

PHH, DSP, and KM are employees of Pfizer Inc.

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Hsyu, PH., Pignataro, D.S. & Matschke, K. Effect of bosutinib on the absorption of dabigatran etexilate mesylate, a P-glycoprotein substrate, in healthy subjects. Eur J Clin Pharmacol 73, 57–63 (2017). https://doi.org/10.1007/s00228-016-2115-0

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  • DOI: https://doi.org/10.1007/s00228-016-2115-0

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