Effects of Concomitant Medication Use on Gefitinib‐Induced Hepatotoxicity

Abstract

Gefitinib is a drug used for the treatment of non-small cell lung cancer (NSCLC) patients. Severe hepatotoxicity was observed, but only a few cases have been reported on the hepatotoxicity of gefitinib. This study aimed to investigate the association between gefitinib-induced hepatotoxicity and various factors including concomitant medications in lung cancer patients. From January 2013 to December 2014, a retrospective study was performed with NSCLC patients who were treated with gefitinib. Associations between hepatotoxicity and various factors including concomitant drugs were analyzed. Based on multivariate models, it was found that H2 antagonists, proton pump inhibitors (PPIs), and H2 antagonists or PPIs increased hepatotoxicity by about 1.5- to 1.7-fold. Patients younger than 65 years showed 1.6 times higher hepatotoxicity than those older than 65 years. Patients with EGFR mutations had around 2-fold higher hepatotoxicity, and the percentage of incidence of hepatotoxicity because of exon 19 deletion was 32.7%. Our study showed that anti-acid-secreting agents in addition to age younger than 65 years and EGFR mutation were associated with gefitinib-induced hepatotoxicity. Thus, close monitoring of liver function is recommended, especially for patients using anti-acid-secreting agents.

Risk factors for erlotinib-induced hepatotoxicity: a retrospective follow-up study

“…Age 65 years and older was a risk factor for hepatotoxicity in the subgroup analysis of NSCLC patients, which contrasted with our previous gefitinib study correlating younger age with higher hepatotoxicity [ 13 ]. Considering that older individuals are usually more vulnerable to drug-induced diseases, the erlotinib result was not a surprise.…”

“…Erlotinib, one of the EGFR TKIs, is also oxidized to reactive epoxide and quinone-imine by cytochrome P450 [ 10 ]. In our previous study [ 13 ], CYP3A4 inducer was one of the significant factors underlying hepatotoxicity in NSCLC patients receiving gefitinib treatment in univariate analysis, although statistical significance was not observed in multivariate analysis. Similarly, combination of lapatinib and dexamethasone, one of the CYP3A4 inducers, showed 4.6-fold and 3.5-fold increased risk of hepatotoxicity and clinically important changes in ALT, respectively [ 14 ].…”

Impact of Use of Gastric-Acid Suppressants and Oral Anticancer Agents on Survival Outcomes: A Systematic Review and Meta-Analysis

“…The first is that combined use of PPIs and TKIs may increase the treatmentrelated adverse events (AEs) of both drugs. Although intuitive, also this mechanism is controversial: in a recent report from Cho et al, concomitant GAS therapy increased gefitinib-induced hepatotoxicity [38]. However, another case series of patients treated with gefitinib and erlotinib did not show differences in the incidence of cutaneous AEs and diarrhea, when comparing patients receiving concomitant GAS to those who did not [30].…”

Impact of Use of Gastric-Acid Suppressants and Oral Anticancer Agents on Survival Outcomes: A Systematic Review and Meta-Analysis

“…The first is that combined use of PPIs and TKIs may increase the treatment-related adverse events (AEs) of both drugs. Although intuitive, also this mechanism is controversial: in a recent report from Cho et al, concomitant GAS therapy increased gefitinib-induced hepatotoxicity [38]. However, another case series of patients treated with gefitinib and erlotinib did not show differences in the incidence of cutaneous AEs and diarrhea, when comparing patients receiving concomitant GAS to those who did not [30].…”