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Comparison of the pharmacokinetics of erlotinib administered in complete fasting and 2 h after a meal in patients with lung cancer

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Abstract

Background

The recommended dose of erlotinib is 150 mg daily either 1 h before a meal (complete fasting) or 2 h after a meal (2 h post-meal), because of the food effect.

Methods

We conducted a cross-over pharmacokinetic study to compare the fed bioequivalence in the two conditions.

Results

Twenty-three patients with non-small cell lung cancer were included in the analysis. AUC0–24 and C max in the 2-h post-meal status were significantly higher than in the complete fasting status (GMR = 1.33, P < 0.001; GMR = 1.44, P < 0.001, respectively). However, because the concentration of erlotinib did not reach the steady state within 7 days in the complete fasting state, we conducted analyses only on day 14, which showed no significant difference in AUC0–24 or C max between the two conditions. The more rapid increase in AUC0–24 and C min did not produce any earlier and more severe toxic events.

Conclusion

The AUC0–24 increased significantly faster (48–53 % greater) in the 2-h post-meal status than in complete fasting status, which suggested that the two gastric emptying states might differ in their absorption. However, there was no clinically significant difference in bioavailability or toxicity between the two clinically used fed conditions at least in 14 days.

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References

  1. Mathijssen RH, Sparreboom A, Verweij J (2014) Determining the optimal dose in the development of anticancer agents. Nat Rev Clin Oncol 11(5):272–281

    Article  CAS  PubMed  Google Scholar 

  2. Szmulewitz RZ, Ratain MJ (2013) Playing Russian roulette with tyrosine kinase inhibitors. Clin Pharmacol Ther 93(3):242–244

    Article  CAS  PubMed  Google Scholar 

  3. Singh BN, Malhotra BK (2004) Effects of food on the clinical pharmacokinetics of anticancer agents: underlying mechanisms and implications for oral chemotherapy. Clin Pharmacokinet 43(15):1127–1156

    Article  CAS  PubMed  Google Scholar 

  4. Ratain MJ (2011) Flushing oral oncology drugs down the toilet. J Clin Oncol 29(30):3958–3959

    Article  PubMed  Google Scholar 

  5. Sparreboom, A. and S.D. Baker, Pharmacokinetic studies in early anticancer drug development in Principles of Anticancer Drug Development. 2011: Humana Press/Springer Science

  6. Ling J et al (2008) Effect of food on the pharmacokinetics of erlotinib, an orally active epidermal growth factor receptor tyrosine-kinase inhibitor, in healthy individuals. Anticancer Drugs 19(2):209–216

    Article  CAS  PubMed  Google Scholar 

  7. Yamamoto N et al (2008) Phase I dose-finding and pharmacokinetic study of the oral epidermal growth factor receptor tyrosine kinase inhibitor Ro50-8231 (erlotinib) in Japanese patients with solid tumors. Cancer Chemother Pharmacol 61(3):489–496

    Article  CAS  PubMed  Google Scholar 

  8. Hidalgo M et al (2001) Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19(13):3267–3279

    CAS  PubMed  Google Scholar 

  9. Soreide E et al (1996) Gastric emptying of a light hospital breakfast. A study using real time ultrasonography. Acta Anaesthesiol Scand 40(5):549–553

    Article  CAS  PubMed  Google Scholar 

  10. Tsuchiya K et al (2014) Low raltegravir concentration in cerebrospinal fluid in patients with ABCG2 genetic variants. J Acquir Immune Defic Syndr 66(5):484–486

    Article  CAS  PubMed  Google Scholar 

  11. Lu JF et al (2006) Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther 80(2):136–145

    Article  CAS  PubMed  Google Scholar 

  12. Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48(3):452–458

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Hamilton M et al (2006) Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 12(7 Pt 1):2166–2171

    Article  CAS  PubMed  Google Scholar 

  14. Nakagawa K et al (2012) Postmarketing surveillance study of erlotinib in Japanese patients with non-small-cell lung cancer (NSCLC): an interim analysis of 3488 patients (POLARSTAR). J Thorac Oncol 7(8):1296–1303

    Article  CAS  PubMed  Google Scholar 

  15. Fukudo M et al (2013) Population pharmacokinetics/pharmacodynamics of erlotinib and pharmacogenomic analysis of plasma and cerebrospinal fluid drug concentrations in Japanese patients with non-small cell lung cancer. Clin Pharmacokinet 52(7):593–609

    Article  CAS  PubMed  Google Scholar 

  16. Rudin CM et al (2008) Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol 26(7):1119–1127

    Article  CAS  PubMed  Google Scholar 

  17. Fujita K et al (2014) High exposure to erlotinib and severe drug-induced interstitial lung disease in patients with non-small-cell lung cancer. Lung Cancer 86(1):113–114

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We wish to thank all the patients who participated in this study and their families. We also wish to thank the staff of Department of Thoracic Oncology, National Cancer Center Hospital. This study was supported by the National Cancer Center Research and Development Fund (23-A-16) from the Ministry of Health, Labor, and Welfare of Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan

    Yuki Katsuya, Yutaka Fujiwara, Kuniko Sunami, Hirofumi Utsumi, Yasushi Goto, Shintaro Kanda, Hidehito Horinouchi, Hiroshi Nokihara, Noboru Yamamoto, Yuichiro Ohe & Tomohide Tamura

  2. Department of Clinical Pharmacology, Center for Translational Research Core, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan

    Yuki Takashima, Satoko Osawa & Akinobu Hamada

  3. Department of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan

    Yutaka Fujiwara, Noboru Yamamoto & Akinobu Hamada

Authors
  1. Yuki Katsuya
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  2. Yutaka Fujiwara
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  3. Kuniko Sunami
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  4. Hirofumi Utsumi
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  5. Yasushi Goto
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  7. Hidehito Horinouchi
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  9. Noboru Yamamoto
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  10. Yuki Takashima
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  11. Satoko Osawa
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  12. Yuichiro Ohe
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  13. Tomohide Tamura
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  14. Akinobu Hamada
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Corresponding author

Correspondence to Yutaka Fujiwara.

Appendix

Appendix

See Table 5 and Figs. 3, 4 and 5.

Table 5 Comparison with previous reports of pharmacokinetics and administration with food
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Fig. 3
figure 3

Schedule of the two cohorts and blood sampling in our study. White arrows show the days when patients were taken blood samples just before taking erlotinib, and black arrows show the days when patients were taken blood samples at 1, 2, 4, 6, 8, 20, and 24 h after taking erlotinib

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Fig. 4
figure 4

Temporal changes in plasma trough concentrations (C min) of erlotinib in each cohort. On day 7, C min in cohort A was significantly higher than in cohort B (P = 0.017), though there was no significant difference on day 14 (P = 0.653). The trough plasma concentration of erlotinib had reached within 7 days only in 2-h post-meal condition. Box-and-whisker plots: The bottom and top of the box are the first and third quartiles, and the band inside the box is the second quartile (the median). The ends of the whiskers represent the lowest datum still within 1.5 interquartile range (IQR) of the lower quartile and the highest datum still within 1.5 IQR of the upper quartile

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Fig. 5
figure 5

Temporal change in AUC0–24 to estimate a two-factor interaction The crossing lines demonstrate that the interaction between the two factors (days 7 or 14, and complete fasting or 2 h post-meal) was cancel effect

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Katsuya, Y., Fujiwara, Y., Sunami, K. et al. Comparison of the pharmacokinetics of erlotinib administered in complete fasting and 2 h after a meal in patients with lung cancer. Cancer Chemother Pharmacol 76, 125–132 (2015). https://doi.org/10.1007/s00280-015-2778-8

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  • DOI: https://doi.org/10.1007/s00280-015-2778-8

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