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Pharmacokinetic parameters of gefitinib predict efficacy and toxicity in patients with advanced non-small cell lung cancer harboring EGFR mutations

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Abstract

Purpose

The relationship between plasma concentration and antitumor activity of gefitinib was assessed in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations.

Patients and methods

Plasma trough levels of gefitinib were measured on days 2 (D2) and 8 (D8) by high-performance liquid chromatography in 31 patients. Plasma concentrations of gefitinib were also measured 10 h after the first administration in 21 of these patients to calculate the elimination half-life of gefitinib.

Results

The median trough levels were: 197 ng/ml 10 h from the first administration of gefitinib; 113 ng/ml on D2; and 358 ng/ml on D8. The median D8/D2 ratio was 2.709, and the median elimination half-life was 15.7 h. The median progression-free survival (PFS) was 273 days, and the median overall survival (OS) was 933 days. A high D8/D2 ratio was significantly correlated with better PFS, though the plasma trough levels on D2 and D8 were not significantly related to PFS. The elimination half-life was not a significant factor for PFS, but it was significantly correlated with high-grade adverse events. Pharmacokinetic parameters were not significantly correlated with OS.

Conclusions

A high D8/D2 ratio, but not elimination half-life, might be a predictor of better PFS in patients with NSCLC harboring EGFR mutations treated with gefitinib. On the other hand, long elimination half-life was related to high-grade adverse events in these patients.

Clinical Trial Registration UMIN000001066.

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References

  1. Maemondo M, Inoue A, Kobayashi K et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388

    Article  CAS  PubMed  Google Scholar 

  2. Mitsudomi T, Morita S, Yatabe Y et al (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

    Article  CAS  PubMed  Google Scholar 

  3. Zhao YY, Li S, Zhang Y et al (2011) The relationship between drug exposure and clinical outcomes of non-small cell lung cancer patients treated with gefitinib. Med Oncol 28:697–702

    Article  CAS  PubMed  Google Scholar 

  4. Hirano S, Sano K, Takeda Y et al (2012) The pharmacokinetics and long-term therapeutic effects of gefitinib in patients with lung adenocarcinoma harboring the epidermal growth factor receptor (EGFR) mutation. Gan To Kagaku Ryoho 39:1501–1506

    CAS  PubMed  Google Scholar 

  5. Nakamura Y, Sano K, Soda H et al (2012) Pharmacokinetics of gefitinib predicts antitumor activity for advanced non-small cell lung cancer. J Thorac Oncol 5:1404–1409

    Article  Google Scholar 

  6. Uesugi T, Sano K, Uesawa Y et al (1997) Ion-pair reversed-phase high-performance liquid chromatography of adenine nucleotides and nucleoside using triethylamine as a counterion. J Chromatogr B Biomed Sci Appl 703:63–74

    Article  CAS  PubMed  Google Scholar 

  7. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  CAS  PubMed  Google Scholar 

  8. Motoshima K, Nakamura Y, Sano K (2013) Phase II trial of erlotinib in patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations: additive analysis of pharmacokinetics. Cancer Chemother Pharmacol 72:1299–1304

    Article  CAS  PubMed  Google Scholar 

  9. Scholler J, Leveque D (2011) Molecular pharmacokinetic determinants of anticancer kinase inhibitors in humans. Oncol Rev 5:77–92

    Article  Google Scholar 

  10. Scheffler M, Di Gion P, Doroshyenko O et al (2011) Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on 4-anilinoquinazolines. Clin Pharmacokinet 50:371–403

    Article  CAS  PubMed  Google Scholar 

  11. Sunaga N, Oriuchi N, Kaira K et al (2008) Usefulness of FDG-PET for early prediction of the response to gefitinib in non-small cell lung cancer. Lung Cancer 59:203–210

    Article  PubMed  Google Scholar 

Download references

Authors contribution

K. M. and Y. N. participated in study design and drafted the manuscript. S. S. was responsible for the statistical analysis and data interpretation. K. S., Y. I., K. M., S. T., D. O., H. S., N. T., T. I., H. Y., K. N., M. F., and H. M. collected clinical data. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan

    Kosuke Mizoguchi, Yoichi Nakamura, Kohei Motoshima, Shinnosuke Takemoto, Daiki Ogawara, Hiroaki Senju, Takaya Ikeda, Hiroyuki Yamaguchi, Katsumi Nakatomi & Hiroshi Mukae

  2. Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Kosuke Mizoguchi & Koichi Izumikawa

  3. Department of Drug Metabolism and Disposition, Meiji Pharmaceutical University, Tokyo, Japan

    Kazumi Sano & Yoji Ikegami

  4. Clinical Research Center, Nagasaki University Hospital, Nagasaki, Japan

    Shuntaro Sato

  5. Department of Respiratory Medicine, Nagasaki Prefecture Shimabara Hospital, Shimabara, Japan

    Nanae Sugasaki

  6. Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan

    Minoru Fukuda

  7. Department of Medical Oncology, Division of Thoracic Oncology, Tochigi Cancer Center, 4-9-13 Yohnan, Utsunomiya, Japan

    Yoichi Nakamura

Authors
  1. Kosuke Mizoguchi
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  2. Yoichi Nakamura
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  3. Kazumi Sano
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  4. Shuntaro Sato
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  5. Yoji Ikegami
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  6. Kohei Motoshima
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  7. Shinnosuke Takemoto
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  8. Daiki Ogawara
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  9. Hiroaki Senju
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  10. Nanae Sugasaki
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  11. Takaya Ikeda
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  12. Hiroyuki Yamaguchi
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  13. Katsumi Nakatomi
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  14. Minoru Fukuda
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  15. Koichi Izumikawa
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  16. Hiroshi Mukae
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Corresponding author

Correspondence to Yoichi Nakamura.

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Conflict of interest

K. M., Y. N., K. S., S. S., Y. I., K. M., S. T., D. O., H. S., N. T., T. I., H. Y., K. N., M. F., and H. M.: none to declare.

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Mizoguchi, K., Nakamura, Y., Sano, K. et al. Pharmacokinetic parameters of gefitinib predict efficacy and toxicity in patients with advanced non-small cell lung cancer harboring EGFR mutations. Cancer Chemother Pharmacol 78, 377–382 (2016). https://doi.org/10.1007/s00280-016-3097-4

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  • DOI: https://doi.org/10.1007/s00280-016-3097-4

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