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



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.


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.


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%).


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.


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



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


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.


  1. 1.
    American Cancer Society (2018) Key statistics for lung cancer. American Cancer Society. Accessed 26 Aug 2018
  2. 2.
    Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK (2014) Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 14:535–546. CrossRefGoogle Scholar
  3. 3.
    Hofman P (2017) ALK in non-small cell lung cancer (NSCLC) pathobiology, epidemiology, detection from tumor tissue and algorithm diagnosis in a daily practice. Cancers (Basel) 9:pii: E107.
  4. 4.
    Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y (2012) RET, ROS1 and ALK fusions in lung cancer. Nat Med 18:378–381. CrossRefGoogle Scholar
  5. 5.
    Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566. CrossRefGoogle Scholar
  6. 6.
    Herbst RS, Morgensztern D, Boshoff C (2018) The biology and management of non-small cell lung cancer. Nature 553:446–454. CrossRefGoogle Scholar
  7. 7.
    McDermott U, Iafrate AJ, Gray NS, Shioda T, Classon M, Maheswaran S, Zhou W, Choi HG, Smith SL, Dowell L, Ulkus LE, Kuhlmann G, Greninger P, Christensen JG, Haber DA, Settleman J (2008) Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 68:3389–3395. CrossRefGoogle Scholar
  8. 8.
    Settleman J (2009) Cell culture modeling of genotype-directed sensitivity to selective kinase inhibitors: targeting the anaplastic lymphoma kinase (ALK). Semin Oncol 36:S36–S41. CrossRefGoogle Scholar
  9. 9.
    Yasuda H, de Figueiredo-Pontes LL, Kobayashi S, Costa DB (2012) Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer. J Thorac Oncol 7:1086–1090. CrossRefGoogle Scholar
  10. 10.
    Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, Iafrate AJ (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30:863–870. CrossRefGoogle Scholar
  11. 11.
    Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G (2007) Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 6:3314–3322. CrossRefGoogle Scholar
  12. 12.
    XALKORI® (crizotinib): US prescribing information. New York, NY: Pfizer Inc (2018)Google Scholar
  13. 13.
    Xalkori® (crizotinib): EMA annex I: summary of product characteristics. Pfizer Europe MA EEIG. Accessed 4 Mar 2019
  14. 14.
    Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, Janne PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner K, Clark JW, Shaw AT (2012) Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 13:1011–1019. CrossRefGoogle Scholar
  15. 15.
    Crinò L, Kim D, Riely GJ, Janne PA, Blackhall FH, Camidge DR, Hirsh V, Mok T, Solomon BJ, Park K, Gadgeel SM, Martins R, Han J, De Pas TM, Bottomley A, Polli A, Petersen J, Tassell VR, Shaw AT (2011) Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol 29(Suppl 15):7514CrossRefGoogle Scholar
  16. 16.
    Kim D-W, Ahn M-J, Shi Y, De Pas TM, Yang P-C, Riely GJ, Crinò L, Evans TL, Liu X, Han J-Y, Salgia R, Moro-Sibilot D, Ignatius Ou SH, Gettinger SN, Wu YL, Lanzalone S, Polli A, Iyer S, Shaw AT (2012) Results of a global phase II study with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol 30(Suppl 15):7533Google Scholar
  17. 17.
    Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O’Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Janne PA (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385–2394. CrossRefGoogle Scholar
  18. 18.
    Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, Zhou C, Shreeve SM, Selaru P, Polli A, Schnell P, Wilner KD, Wiltshire R, Camidge DR, Crino L (2015) Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol 33:1881–1888. CrossRefGoogle Scholar
  19. 19.
    Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ (2014) Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963–1971. CrossRefGoogle Scholar
  20. 20.
    Yoneda KY, Scranton JR, Cadogan MA, Tassell V, Nadanaciva S, Wilner KD, Stollenwerk NS (2017) Interstitial lung disease associated with crizotinib in patients with advanced non-small cell lung cancer: independent review of four PROFILE trials. Clin Lung Cancer 18:472–479. CrossRefGoogle Scholar
  21. 21.
    Johnson TR, Tan W, Goulet L, Smith EB, Yamazaki S, Walker GS, O’Gorman MT, Bedarida G, Zou HY, Christensen JG, Nguyen LN, Shen Z, Dalvie D, Bello A, Smith BJ (2015) Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects. Xenobiotica 45:45–59. CrossRefGoogle Scholar
  22. 22.
    Yamazaki S, Johnson TR, Smith BJ (2015) Prediction of drug-drug interactions with crizotinib as the CYP3A substrate using a physiologically based pharmacokinetic model. Drug Metab Dispos 43:1417–1429. CrossRefGoogle Scholar
  23. 23.
    Xu H, O’Gorman M, Tan W, Brega N, Bello A (2015) The effects of ketoconazole and rifampin on the single-dose pharmacokinetics of crizotinib in healthy subjects. Eur J Clin Pharmacol 71:1441–1449. CrossRefGoogle Scholar
  24. 24.
    Luo G, Cunningham M, Kim S, Burn T, Lin J, Sinz M, Hamilton G, Rizzo C, Jolley S, Gilbert D, Downey A, Mudra D, Graham R, Carroll K, Xie J, Madan A, Parkinson A, Christ D, Selling B, LeCluyse E, Gan LS (2002) CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos 30:795–804CrossRefGoogle Scholar
  25. 25.
    Iwanaga K, Honjo T, Miyazaki M, Kakemi M (2013) Time-dependent changes in hepatic and intestinal induction of cytochrome P450 3A after administration of dexamethasone to rats. Xenobiotica 43:765–773. CrossRefGoogle Scholar
  26. 26.
    Lu C, Li AP (2001) Species comparison in P450 induction: effects of dexamethasone, omeprazole, and rifampin on P450 isoforms 1A and 3A in primary cultured hepatocytes from man, Sprague-Dawley rat, minipig, and beagle dog. Chem Biol Interact 134:271–281CrossRefGoogle Scholar
  27. 27.
    McCune JS, Hawke RL, LeCluyse EL, Gillenwater HH, Hamilton G, Ritchie J, Lindley C (2000) In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone. Clin Pharmacol Ther 68:356–366. CrossRefGoogle Scholar
  28. 28.
    Hachad H, Ragueneau-Majlessi I, Levy RH (2010) A useful tool for drug interaction evaluation: the University of Washington Metabolism and Transport Drug Interaction Database. Hum Genomics 5:61–72CrossRefGoogle Scholar
  29. 29.
    Cagney DN, Martin AM, Catalano PJ, Redig AJ, Lin NU, Lee EQ, Wen PY, Dunn IF, Bi WL, Weiss SE, Haas-Kogan DA, Alexander BM, Aizer AA (2017) Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol 19:1511–1521. CrossRefGoogle Scholar
  30. 30.
    Tsakonas G, De Petris L, Ekman S (2017) Management of brain metastasized non-small cell lung cancer (NSCLC)—from local treatment to new systemic therapies. Cancer Treat Rev 54:122–131. CrossRefGoogle Scholar
  31. 31.
    Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, Uhlmann EJ, Wong ET, Dahlberg SE, Huberman MS, Costa DB (2015) Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 88:108–111. CrossRefGoogle Scholar
  32. 32.
    Crinò L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, Mok T, Spigel D, Felip E, Nishio M, Scagliotti G, Branle F, Emeremni C, Quadrigli M, Zhang J, Shaw AT (2016) Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2. J Clin Oncol 34:2866–2873. CrossRefGoogle Scholar
  33. 33.
    Doebele RC, Lu X, Sumey C, Maxson DA, Weickhardt AJ, Oton AB, Bunn PA Jr, Baron AE, Franklin WA, Aisner DL, Varella-Garcia M, Camidge DR (2012) Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer. Cancer 118:4502–4511. CrossRefGoogle Scholar
  34. 34.
    Davey P (2002) Brain metastases: treatment options to improve outcomes. CNS Drugs 16:325–338CrossRefGoogle Scholar
  35. 35.
    Lin X, DeAngelis LM (2015) Treatment of brain metastases. J Clin Oncol 33:3475–3484. CrossRefGoogle Scholar
  36. 36.
    Wooldridge JE, Anderson CM, Perry MC (2001) Corticosteroids in advanced cancer. Oncology (Williston Park) 15:225–236Google Scholar
  37. 37.
    Ryken TC, McDermott M, Robinson PD, Ammirati M, Andrews DW, Asher AL, Burri SH, Cobbs CS, Gaspar LE, Kondziolka D, Linskey ME, Loeffler JS, Mehta MP, Mikkelsen T, Olson JJ, Paleologos NA, Patchell RA, Kalkanis SN (2010) The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 96:103–114. CrossRefGoogle Scholar
  38. 38.
    Soffietti R, Abacioglu U, Baumert B, Combs SE, Kinhult S, Kros JM, Marosi C, Metellus P, Radbruch A, Villa Freixa SS, Brada M, Carapella CM, Preusser M, Le Rhun E, Ruda R, Tonn JC, Weber DC, Weller M (2017) Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol 19:162–174. CrossRefGoogle Scholar
  39. 39.
    Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, Martinez-Bernal G, Ferrara R, Lai WV, Hendriks LEL, Sabari JK, Caramella C, Plodkowski AJ, Halpenny D, Chaft JE, Planchard D, Riely GJ, Besse B, Hellmann MD (2018) Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 36:2872–2878. CrossRefGoogle Scholar

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

Personalised recommendations