Factors affecting time to reach and recover from gefitinib-induced hepatotoxicity

Gefitinib is an oral tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) for non-small-cell lung cancer with EGFR mutations. Although a few studies have analyzed the causes of gefitinib-induced hepatotoxicity, research focusing on the time intervals before and after hepatotoxicity has yet to be reported. Therefore, this study investigated two types of factors: the time to reach gefitinib-induced hepatotoxicity and the time for recovery. From January 2013 to December 2014, a retrospective study was carried out on 473 non-small-cell lung cancer patients who were treated with gefitinib. The following data were collected: sex, age, body weight, height, body surface area, underlying disease, Eastern Cooperative Oncology Group Performance Status, smoking history, gefitinib dose, EGFR mutation, and concomitant drugs. Multivariate models showed that patients with mutations in exon 19 had around two-fold higher hepatotoxicity (≥grade 2). Use of CYP3A4 inhibitors and smoking shortened time to hepatotoxicity ∼5–2-fold, respectively, whereas mutations in exon 21 prolonged time to hepatotoxicity by about 2.4-fold. Termination of gefitinib therapy showed 3.8-fold faster recovery. Our study showed that the concomitant use of CYP3A4 inhibitors, smoking, and exon 21 affected the time to reach gefitinib-induced hepatotoxicity. Among the factors examined in this study including hepatotonic use and gefitinib termination, only cessation of gefitinib therapy significantly accelerated recovery. Correspondence to Hye Sun Gwak, PharmD, PhD, Division of Life and Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea Tel: +82 2 3277 4376; fax: +82 2 3277 3051; e-mail: hsgwak@ewha.ac.kr Received October 6, 2017 Accepted February 27, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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