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

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

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).

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

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 was obtained from all individual participants included in the study.

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 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, Tadworth, Surrey, KT20 7NS, UK

    Daniela Soriano Pignataro

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

    Kyle Matschke

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  1. Poe-Hirr Hsyu
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  2. Daniela Soriano Pignataro
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  3. Kyle Matschke
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Correspondence to Poe-Hirr Hsyu.

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Hsyu, PH., Pignataro, D.S. & Matschke, K. Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects. Eur J Clin Pharmacol 73, 49–56 (2017). https://doi.org/10.1007/s00228-016-2108-z

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  • DOI: https://doi.org/10.1007/s00228-016-2108-z

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