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Impact of histamine type-2 receptor antagonists on the anticancer efficacy of gefitinib in patients with non-small cell lung cancer

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

Abstract

Purpose

Gefitinib is one of the standard treatments for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutations. It has been reported that acid suppressants (AS) decrease the anti-tumor effect of gefitinib by reducing its solubility. AS is sometimes necessary in cancer patients; however, previous reports have not shown the most compatible AS with gefitinib administration in cancer patients. This study was conducted to determine if histamine type 2 receptor antagonists (H2RAs) can affect the anti-tumor efficacy of gefitinib.

Methods

Eighty-seven patients with NSCLC who were administered gefitinib were retrospectively investigated. Patients who were co-administered H2RA were compared with non-AS control patients. H2RA was administered once a day at about 3–5 or 8–12 h after gefitinib intake. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR), and adverse effects.

Results

Median PFS in H2RA group and control group was 8.0 months and 9.0 months, respectively, with no significant difference (p = 0.82). The incidence of liver dysfunction was significantly less in patients administered H2RA, whereas there were no differences between the two groups with regard to skin toxicity and diarrhea. Multivariate analysis suggested that H2RA co-administration is not a risk factor for worse PFS and OS (hazard ratio of 0.95, 0.86; 95% confidence interval of 0.60–1.48, 0.52–1.43; p = 0.82 and 0.60, respectively).

Conclusion

This study demonstrated that concomitant administration of H2RA with gefitinib does not affect the efficacy of gefitinib.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T, North-East Japan Study Group (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388. https://doi.org/10.1056/NEJMoa0909530

    Article  CAS  PubMed  Google Scholar 

  2. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M, West Japan Oncology Group (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11:121–128. https://doi.org/10.1016/S1470-2045(09)70364-X

    Article  CAS  PubMed  Google Scholar 

  3. Midha A, Dearden S, McCormack R (2015) EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 5:2892–2911

    PubMed  PubMed Central  Google Scholar 

  4. Shiraishi K, Okada Y, Takahashi A, Kamatani Y, Momozawa Y, Ashikawa K, Kunitoh H, Matsumoto S, Takano A, Shimizu K, Goto A, Tsuta K, Watanabe S, Ohe Y, Watanabe Y, Goto Y, Nokihara H, Furuta K, Yoshida A, Goto K, Hishida T, Tsuboi M, Tsuchihara K, Miyagi Y, Nakayama H, Yokose T, Tanaka K, Nagashima T, Ohtaki Y, Maeda D, Imai K, Minamiya Y, Sakamoto H, Saito A, Shimada Y, Sunami K, Saito M, Inazawa J, Nakamura Y, Yoshida T, Yokota J, Matsuda F, Matsuo K, Daigo Y, Kubo M, Kohno T (2016) Association of variations in HLA class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma. Nat Commun 7:12451. https://doi.org/10.1038/ncomms12451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kudo K, Hotta K, Ichihara E, Yoshioka H, Kunimasa K, Tsubouchi K, Iwasaku M, Kato Y, Oze I, Takigawa N, Tanimoto M, Kiura K (2015) Impact of body surface area on survival in EGFR-mutant non-small cell lung cancer patients treated with gefitinib monotherapy: observational study of the Okayama Lung Cancer Study Group 0703. Cancer Chemother Pharmacol 76:251–256. https://doi.org/10.1007/s00280-015-2789-5

    Article  CAS  PubMed  Google Scholar 

  6. Ichihara E, Hotta K, Takigawa N, Kudo K, Kato Y, Honda Y, Hayakawa H, Minami D, Sato A, Tabata M, Tanimoto M, Kiura K (2013) Impact of physical size on gefitinib efficacy in patients with non-small cell lung cancer harboring EGFR mutations. Lung Cancer 81:435–439. https://doi.org/10.1016/j.lungcan.2013.05.021

    Article  PubMed  Google Scholar 

  7. Igawa S, Kasajima M, Ishihara M, Kimura M, Hiyoshi Y, Niwa H, Kusuhara S, Harada S, Asakuma M, Otani S, Katono K, Sasaki J, Masuda N (2014) Evaluation of gefitinib efficacy according to body surface area in patients with non-small cell lung cancer harboring an EGFR mutation. Cancer Chemother Pharmacol 74:939–946. https://doi.org/10.1007/s00280-014-2570-1

    Article  CAS  PubMed  Google Scholar 

  8. Imai H, Kuwako T, Kaira K, Masuda T, Miura Y, Seki K, Sakurai R, Utsugi M, Shimizu K, Sunaga N, Tomizawa Y, Ishihara S, Ishizuka T, Mogi A, Hisada T, Minato K, Takise A, Saito R, Yamada M (2017) Evaluation of gefitinib efficacy according to body mass index, body surface area, and body weight in patients with EGFR-mutated advanced non-small cell lung cancer. Cancer Chemother Pharmacol 79:497–505. https://doi.org/10.1007/s00280-016-3232-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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. https://doi.org/10.1021/mp400403s

    Article  CAS  PubMed  Google Scholar 

  10. 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. https://doi.org/10.1038/clpt.2014.87

    Article  CAS  PubMed  Google Scholar 

  11. European Medicines Agency. Iressa: summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001016/WC500036358.pdf. Accessed 7 Aug 2018

  12. Chu MP, Ghosh S, Chambers CR, Basappa N, Butts CA, Chu Q, Fenton D, Joy AA, Sangha R, Smylie M, Sawyer MB (2015) Gastric acid suppression is associated with decreased erlotinib efficacy in non-small-cell lung cancer. Clin Lung Cancer 16:33–39. https://doi.org/10.1016/j.cllc.2014.07.005

    Article  CAS  PubMed  Google Scholar 

  13. Zenke Y, Yoh K, Matsumoto S, Umemura S, Niho S, Ohmatsu H, Goto K, Ohe Y (2016) Clinical impact of gastric acid-suppressing medication use on the efficacy of erlotinib and gefitinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations. Clin Lung Cancer 17:412–418. https://doi.org/10.1016/j.cllc.2016.01.006

    Article  CAS  PubMed  Google Scholar 

  14. Kumarakulasinghe NB, Syn N, Soon YY, Asmat A, Zheng H, Loy EY, Pang B, Soo RA (2016) EGFR kinase inhibitors and gastric acid suppressants in EGFR-mutant NSCLC: a retrospective database analysis of potential drug interaction. Oncotarget 7:85542–85550. https://doi.org/10.18632/oncotarget.13458

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hilton JF, Tu D, Seymour L, Shepherd FA, Bradbury PA (2013) An evaluation of the possible interaction of gastric acid suppressing medication and the EGFR tyrosine kinase inhibitor erlotinib. Lung Cancer 82:136–142. https://doi.org/10.1016/j.lungcan.2013.06.008

    Article  CAS  PubMed  Google Scholar 

  16. Lim SG, Sawyerr AM, Hudson M, Sercombe J, Pounder RE (1993) Short report: the absorption of fluconazole and itraconazole under conditions of low intragastric acidity. Aliment Pharmacol Ther 7:317–321

    Article  CAS  Google Scholar 

  17. Jaruratanasirikul S, Sriwiriyajan S (1998) Effect of omeprazole on the pharmacokinetics of itraconazole. Eur J Clin Pharmacol 54:159–161

    Article  CAS  Google Scholar 

  18. Uno T, Sugimoto K, Sugawara K, Tateishi T (2008) The role of cytochrome P2C19 in R-warfarin pharmacokinetics and its interaction with omeprazole. Ther Drug Monit 30:276–281. https://doi.org/10.1097/FTD.0b013e31816e2d8e

    Article  CAS  PubMed  Google Scholar 

  19. Narumi K, Sato Y, Kobayashi M, Furugen A, Kasashi K, Yamada T, Teshima T, Iseki K (2017) Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: evaluation of drug-drug interactions mediated by organic anion transporter 3. Biopharm Drug Dispos 38:501–508. https://doi.org/10.1002/bdd.2091

    Article  CAS  PubMed  Google Scholar 

  20. 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. https://doi.org/10.1038/clpt.2012.73

    Article  CAS  PubMed  Google Scholar 

  21. Nakamura Y, Sano K, Soda H, Takatani H, Fukuda M, Nagashima S, Hayashi T, Oka M, Tsukamoto K, Kohno S (2010) Pharmacokinetics of gefitinib predicts antitumor activity for advanced non-small cell lung cancer. J Thorac Oncol 5:1404–1409. https://doi.org/10.1097/JTO.0b013e3181e59a7b

    Article  PubMed  Google Scholar 

  22. Yokota H, Sato K, Okuda Y, Kobayashi H, Takeda M, Asano M, Ito H, Miura M (2017) Effects of histamine 2-receptor antagonists and proton pump inhibitors on the pharmacokinetics of gefitinib in patients with non-small-cell lung cancer. Clin Lung Cancer 18:e433–e439. https://doi.org/10.1016/j.cllc.2017.05.010

    Article  CAS  PubMed  Google Scholar 

  23. Ruiz-Garcia A, Masters JC, Mendes da Costa L, LaBadie RR, Liang Y, Ni G, Ellery CA, Boutros T, Goldberg Z, Bello CL (2016) Effect of food or proton pump inhibitor treatment on the bioavailability of dacomitinib in healthy volunteers. J Clin Pharmacol 56:223–230. https://doi.org/10.1002/jcph.588

    Article  CAS  PubMed  Google Scholar 

  24. Sato T, Ito H, Hirata A, Abe T, Mano N, Yamaguchi H (2018) Interactions of crizotinib and gefitinib with organic anion-transporting polypeptides (OATP)1B1, OATP1B3 and OATP2B1: gefitinib shows contradictory interaction with OATP1B3. Xenobiotica 48:73–78. https://doi.org/10.1080/00498254.2016.1275880

    Article  CAS  PubMed  Google Scholar 

  25. Scheffler M, Di Gion P, Doroshyenko O, Wolf J, Fuhr U (2011) Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on 4-anilinoquinazolines. Clin Pharmacokinet 50:371–403. https://doi.org/10.2165/11587020-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  26. Ozvegy-Laczka C, Hegedus T, Várady G, Ujhelly O, Schuetz JD, Váradi A, Kéri G, Orfi L, Német K, Sarkadi B (2004) High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol 65:1485–1495

    Article  Google Scholar 

  27. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ (2006) Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 12:2166–2171

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan

    Yoshitaka Saito, Yoh Takekuma & Mitsuru Sugawara

  2. Laboratory of Clinical Pharmaceutics & Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo, 060-0812, Japan

    Masaki Kobayashi & Ken Iseki

  3. First Department of Medicine, Hokkaido University School of Medicine, Kita 15-jo, Nishi 7-chome, Kita-ku, Sapporo, 060-8638, Japan

    Naofumi Shinagawa

  4. Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Kita 15-jo, Nishi 7-chome, Kita-ku, Sapporo, 060-8638, Japan

    Yasushi Shimizu, Ichiro Kinoshita & Hirotoshi Dosaka-Akita

  5. Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo, 060-0812, Japan

    Mitsuru Sugawara

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Contributions

Designed study: Y.S., Y.T., M.K., N.S., Y.S., I.K., H.D., K.I., and M.S. Performed research: Y.S. Analyzed data: Y.S., Y.T., M.K. Contributed new methods or models: Y.S., Y.T., M.K. Wrote the paper: Y.S. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Mitsuru Sugawara.

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Competing interests

YS, MK, YT, NS, YS, IK, KI, and MS have no conflicts of interest.

HD received an honorarium from AstraZeneca for speaking at a symposium.

Ethics approval and consent to participate

All the procedures performed in studies involving human participants were carried out 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. For this type of study, formal consent is not required.

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Saito, Y., Takekuma, Y., Kobayashi, M. et al. Impact of histamine type-2 receptor antagonists on the anticancer efficacy of gefitinib in patients with non-small cell lung cancer. Eur J Clin Pharmacol 77, 381–388 (2021). https://doi.org/10.1007/s00228-020-03013-9

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