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Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 1, pp 203–211 | Cite as

Clinical implications of an analysis of pharmacokinetics of crizotinib coadministered with dexamethasone in patients with non-small cell lung cancer

  • Swan Lin
  • Dana J. Nickens
  • Maulik Patel
  • Keith D. Wilner
  • Weiwei TanEmail author
Original Article

Abstract

Purpose

Dexamethasone is a systemic corticosteroid and a known cytochrome P450 (CYP)3A inducer. Crizotinib is a selective tyrosine kinase inhibitor of ALK, ROS1, and MET and a substrate of CYP3A. This post hoc analysis characterized the use of concomitant CYP3A inducers with crizotinib and estimated the effect of dexamethasone use on crizotinib pharmacokinetics at steady state.

Methods

This analysis used data from four clinical studies (PROFILE 1001, 1005, 1007, and 1014) including 1690 patients with non-small cell lung cancer with ALK or ROS1 rearrangements treated with crizotinib at 250 mg twice daily. Frequency and reasons for use of concomitant CYP3A inducers, including dexamethasone, with crizotinib were characterized. Multiple steady-state trough concentrations (Ctrough,ss) of crizotinib were measured for each patient. A linear mixed-effects model was used for within-patient comparison of crizotinib Ctrough,ss between dosing of crizotinib alone and crizotinib coadministered with dexamethasone consecutively for ≥ 21 days.

Results

Dexamethasone was the most commonly used CYP3A inducer (30.4%). A total of 15 patients had crizotinib Ctrough,ss for both crizotinib dosing with and without dexamethasone. The adjusted geometric mean ratio of crizotinib Ctrough,ss following coadministration with dexamethasone relative to crizotinib without dexamethasone, as a percentage, was 98.2% (90% confidence interval, 79.1–122.0%).

Conclusions

Crizotinib plasma exposure following coadministration with dexamethasone was similar to that when crizotinib was administered without dexamethasone, indicating dexamethasone has no effect on crizotinib exposure or efficacy. Other CYP3A inducers with similar potency would likewise have no clinically relevant effect on crizotinib exposure.

Keywords

Crizotinib CYP3A inducers Dexamethasone Non-small cell lung cancer Targeted therapy 

Notes

Acknowledgements

Editorial assistance and manuscript preparation were provided by inScience Communications, Springer Healthcare (Philadelphia, PA, USA) and funded by Pfizer Inc.

Funding

This study was supported by Pfizer Inc.

Compliance with ethical standards

Conflict of interest

S. Lin, D. J. Nickens, K. D. Wilner, and W. Tan are employees of Pfizer. M. Patel was an employee of Pfizer during development of the manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

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

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Swan Lin
    • 1
  • Dana J. Nickens
    • 1
  • Maulik Patel
    • 1
  • Keith D. Wilner
    • 2
  • Weiwei Tan
    • 1
    Email author
  1. 1.Clinical Pharmacology, Global Product DevelopmentPfizer IncSan DiegoUSA
  2. 2.Oncology, Global Product DevelopmentPfizer IncSan DiegoUSA

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