Skip to main content
SpringerLink
Log in

Assessment of drug–drug interaction potential between ceritinib and proton pump inhibitors in healthy subjects and in patients with ALK-positive non-small cell lung cancer

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated.

Methods

A healthy subject drug–drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (Ctrough,ss) and overall response rate (ORR) by concomitant use of PPIs in patients from the ASCEND-1, -2, and -3 studies; analysis 2 evaluated ceritinib single-dose and steady-state AUC0–24h and C max by concomitant PPI use in patients from ASCEND-1 using a definition of PPI usage similar to that used in the healthy subject study.

Results

In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC0–∞ by 76% and C max by 79%. However, based on subgroup analysis 1, patients had similar C trough,ss and ORR regardless of concomitant PPI usage. Based on analysis 2, co-administration of a single 750 mg ceritinib dose with PPIs for 6 days in patients suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC0–24h decreased by 30% and C max decreased by 25%. No clinically meaningful effect on steady-state exposure was observed after daily dosing.

Conclusions

Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. 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. doi:10.1038/nature05945

    Article  CAS  PubMed  Google Scholar 

  2. Ou SH (2011) Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond. Drug Des Devel Ther 5:471–485. doi:10.2147/DDDT.S19045

    Article  PubMed  PubMed Central  Google Scholar 

  3. Scagliotti G, Stahel RA, Rosell R, Thatcher N, Soria JC (2012) ALK translocation and crizotinib in non-small cell lung cancer: an evolving paradigm in oncology drug development. Eur J Cancer 48:961–973. doi:10.1016/j.ejca.2012.02.001

    Article  CAS  PubMed  Google Scholar 

  4. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, Jessop NA, Wain JC, Yeo AT, Benes C, Drew L, Saeh JC, Crosby K, Sequist LV, Iafrate AJ, Engelman JA (2012) Mechanism of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 4:120ra17. doi:10.1126/scitranslmed.3003316

  5. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA, Varella-Garcia M, Camidge DR (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472–1482. doi:10.1158/1078-0432.CCR-11-2906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, Michellys PY, Awad MM, Yanagitani N, Kim S, Pferdekamper AC, Li J, Kasibhatla S, Sun F, Sun X, Hua S, McNamara P, Mahmood S, Lockerman EL, Fujita N, Nishio M, Harris JL, Shaw AT, Engelman JA (2014) The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 4:662–673. doi:10.1158/2159-8290.CD-13-0846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA (2014) Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370:1189–1197. doi:10.1056/NEJMoa1311107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Sutradhar S, Li S, Szczudlo T, Yovine A, Shaw AT (2016) Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol 17:452–463. doi:10.1016/S1470-2045(15)00614-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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. doi:10.1200/JCO.2015.65.5936

    Article  PubMed  Google Scholar 

  10. Felip E, Orlov S, Park K, Yu C-J, Tsai C-M, Nishio M, Dols MC, McKeage M, Su W-C, Mok TSK, Scagliotti G, Spigel DR, Passos VQ, Chen V, Munarini F, Shaw A (2016) Phase 2 study of ceritinib in ALKi-naïve patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC): whole body responses in the overall pt group and in pts with baseline brain metastases (BM). Ann Oncol 27:1208O. doi:10.1093/annonc/mdw383.03

    Article  Google Scholar 

  11. Lau YY, Gu J, Lin T, Song D, Yu R, Scott JW (2016) Effects of meal type on the oral bioavailability of the ALK inhibitor ceritinib in healthy adult subjects. J Clin Pharmacol 56:559–566. doi:10.1002/jcph.619

    Article  CAS  PubMed  Google Scholar 

  12. US Food and Drug Administration (2016) Zykadia prescribing information. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/zykadia.pdf. Accessed 26 Oct 26 2016

  13. European Medicines Agency (2016) Zykadia summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003819/WC500187504.pdf. Accessed 26 Oct 2016

  14. US Food and Drug Administration (2014). Clinical pharmacology and biopharmaceutics review(s) of ceritinib. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205755Orig1s000ClinPharmR.pdf. Accessed 26 Oct 2016

  15. Miner P, Katz PO, Chen Y, Sostek M (2003) Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterol 98:2616–2620. doi:10.1111/j.1572-0241.2003.08783.x

    Article  CAS  PubMed  Google Scholar 

  16. Ogawa R, Echizen H (2010) Drug–drug interaction profiles of proton pump inhibitors. Clin Pharmacokinet 49:509–533. doi:10.2165/11531320-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  17. Zhang L, Wu F, Lee SC, Zhao H, Zhang L (2014) pH-dependent drug-drug interactions for weak base drugs: potential implications for new drug development. Clin Pharmacol Ther 96:266–277. doi:10.1038/clpt.2014.87

    Article  CAS  PubMed  Google Scholar 

  18. Budha NR, Frymoyer A, Smelick GS, Jin JY, Yago MR, Dresser MJ, Holden SN, Benet LZ, Ware JA (2012) Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther 92:203–213. doi:10.1038/clpt.2012.73

    Article  CAS  PubMed  Google Scholar 

  19. Smelick GS, Heffron TP, Chu L, Dean B, West DA, Duvall SL, Lum BL, Budha N, Holden SN, Benet LZ, Frymoyer A, Dresser MJ, Ware JA (2013) Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development. Mol Pharm 10:4055–4062. doi:10.1021/mp400403s

    Article  CAS  PubMed  Google Scholar 

  20. Heudi O, Vogel D, Lau YY, Picard F, Kretz O (2014) Liquid chromatography tandem mass spectrometry method for the quantitative analysis of ceritinib in human plasma and its application to pharmacokinetic studies. Anal Bioanal Chem 406:7389–7396. doi:10.1007/s00216-014-8125-9

    Article  CAS  PubMed  Google Scholar 

  21. Roehss K, Lind T, Wilder-Smith C (2004) Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastro-oesophageal reflux symptoms. Eur J Clin Pharmacol 60:531–539. doi:10.1007/s00228-004-0804-6

    Article  CAS  Google Scholar 

  22. Scott LJ, Dunn CJ, Mallarkey G, Sharpe M (2002) Esomeprazole: a review of its use in the management of acid-related disorders. Drugs 62:1503–1538. doi:10.2165/00003495-200262100-00006

    Article  CAS  PubMed  Google Scholar 

  23. Chremos AN (1987) Clinical pharmacology of famotidine: a summary. J Clin Gastroenterol 9:7–12. doi:10.1097/00004836-198707002-00003

    Article  PubMed  Google Scholar 

  24. Shin JM, Kim N (2013) Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil 19:25–35. doi:10.5056/jnm.2013.19.1.25

    Article  PubMed  PubMed Central  Google Scholar 

  25. US Food and Drug Administration (2000). Pharmacodynamic aspects of H2-blockers versus proton pump inhibitors. http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3650b1b_tab_03.pdf. Accessed 26 Oct 2016

  26. Yin OQ, Giles FJ, Baccarani M, le Coutre P, Chiparus O, Gallagher N, Saglio G, Hughes TP, Hochhaus A, Kantarjian HM, Larson RA (2012) Concurrent use of proton pump inhibitors or H2 blockers did not adversely affect nilotinib efficacy in patients with chronic myeloid leukemia. Cancer Chemother Pharmacol 70:345–350. doi:10.1007/s00280-012-1881-3

    Article  CAS  PubMed  Google Scholar 

  27. Ramanathan S, Jin F, Sharma S, Kearney BP (2015) Clinical pharmacokinetic and pharmacodynamics profile of idelalisib. Clin Pharmacokinet 55:33–45. doi:10.1007/s40262-015-0304-0

    Article  Google Scholar 

  28. Hong Y, Passos VQ, Huang PH, Lau YY (2016) Population pharmacokinetics of ceritinib in adult patients with tumors characterized by genetic abnormalities in anaplastic lymphoma kinase (ALK). J Clin Pharmacol. doi:10.1002/jcph.849

    PubMed  Google Scholar 

  29. Zhu Y, Statkevich P, Cutler DL (2007) Effect of food on the pharmacokinetics of lonafarnib (SCH 66336) following single and multiple doses. Int J Clin Pharmacol Ther 45:539–547. doi:10.5414/CPP45539

    Article  CAS  PubMed  Google Scholar 

  30. Chi KN, Spratlin J, Kollmannsberger C (2015) Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer. J Clin Pharmacol 55:1406–1414. doi:10.1002/jcph.564

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Janet Lasher and Rakesh Kumar for their operational support; Olivier Heudi and Luc Alexis Leuthold for their contribution to sample analysis; the nursing and research staff members at PPD, LLC for their assistance in the conduct of the healthy subject drug–drug interaction study. Medical editorial assistance for this manuscript was provided by Pushkar Narvilkar and Shiva Krishna Rachamadugu, Novartis Healthcare Pvt. Ltd.

Author information

Authors and Affiliations

  1. Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA

    Yvonne Y. Lau, Wen Gu, Tiffany Lin, Kalyanee Viraswami-Appanna, Can Cai, Jeffrey W. Scott & Michael Shi

Authors
  1. Yvonne Y. Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wen Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tiffany Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kalyanee Viraswami-Appanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Can Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeffrey W. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yvonne Y. Lau.

Ethics declarations

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 was obtained from all individual participants included in the study

Conflict of interest

YYL, WG, KV-A, CC, JWS, and MS are employees and stockholders of Novartis Pharmaceuticals Corporation. TL was an employee of Novartis Pharmaceuticals Corporation at the time of this work.

Funding

These studies and analyses were sponsored and supported by Novartis Pharmaceuticals Corporation.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lau, Y.Y., Gu, W., Lin, T. et al. Assessment of drug–drug interaction potential between ceritinib and proton pump inhibitors in healthy subjects and in patients with ALK-positive non-small cell lung cancer. Cancer Chemother Pharmacol 79, 1119–1128 (2017). https://doi.org/10.1007/s00280-017-3308-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-017-3308-7

Keywords

Search

Navigation