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Evaluation of gefitinib systemic exposure in EGFR-mutated non-small cell lung cancer patients with gefitinib-induced severe hepatotoxicity



Severe hepatotoxicity induced by the standard dose of gefitinib (250 mg daily) often becomes manageable by dose reduction to 250 mg every other day. Thus, we hypothesized that systemic exposure of standard-dose gefitinib in patients with experience of severe hepatotoxicity might be higher than that in patients without severe hepatotoxicity.


Patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer who were receiving gefitinib either at a reduced dose (250 mg every other day) because of intolerable severe toxicity or at a standard dose (250 mg daily) were enrolled. A series of blood samples were collected to estimate pharmacokinetic parameters and calculate systemic exposure of standard-dose gefitinib (area under the concentration–time curve from 0 to 24 h at steady state, AUC0–24,ss). Systemic exposure of unbound gefitinib (fu·AUC0–24,ss) was also assessed, because gefitinib is extensively bound to serum proteins.


Of the 38 enrolled patients, 34 (23 patients without experience of severe hepatotoxicity, 11 patients with experience of severe hepatotoxicity) were evaluable. There was no significant differences in total AUC0–24,ss or unbound fu·AUC0–24,ss between patients with and without experience of severe hepatotoxicity. Analysis of the time to severe hepatotoxicity indicated no difference between patients with a high AUC0–24,ss and those with a low AUC0–24,ss of either total or unbound gefitinib.


This study suggests that reversible severe hepatotoxicity is not caused by high systemic exposure of gefitinib.

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This work was supported by JSPS KAKENHI Grant Number JP16K09568. We thank all the patients who participated in this study and their families. We also thank Ms. Mie Yamada, Ms. Chiemi Asano, and Ms. Miho Watanabe (Division of Thoracic Oncology, Shizuoka Cancer Center) for study management; Ms. Yumiko Iwamoto, Ms. Yumi Oguma, Ms. Masayo Kaneko, Ms. Satomi Koizumi, and Ms. Yukako Kawano (Nursing Department, Shizuoka Cancer Center) for blood sampling; and Dr. Haruki Kobayashi, Dr. Norimitsu Kasahara, Dr. Takumi Fujiwara, Dr. Mie Kotake, and Dr. Nobuaki Mamesaya (Division of Thoracic Oncology, Shizuoka Cancer Center) for their contributions to this study.

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Correspondence to Yusuke Tanigawara.

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Conflict of interest

Chiyo K. Imamura, Hirotsugu Kenmotsu, Shota Omori, Kazushige Wakuda, Haruyasu Murakami, Toshiaki Takahashi, and Yusuke Tanigawara have received honouraria from AstraZeneca. Kazushige Wakuda, Hirotsugu Kenmotsu, and Toshiaki Takahashi have received a grant from AstraZeneca. For the remaining authors, no conflicts of interest are declared. All of the conflicts of interest are outside the submitted work.

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Kawamura, T., Imamura, C.K., Kenmotsu, H. et al. Evaluation of gefitinib systemic exposure in EGFR-mutated non-small cell lung cancer patients with gefitinib-induced severe hepatotoxicity. Cancer Chemother Pharmacol 85, 605–614 (2020). https://doi.org/10.1007/s00280-020-04034-y

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  • Gefitinib
  • Non-small cell lung cancer
  • Pharmacokinetics
  • Protein binding
  • Severe hepatotoxicity
  • Systemic exposure