Purpose: 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. Methods: 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. Results: 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. Conclusion: This study suggests that reversible severe hepatotoxicity is not caused by high systemic exposure of gefitinib.
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