Factors affecting time to reach and recover from gefitinib-induced hepatotoxicity
Yoon Hee Park1,2, Soyeon Cho1,2, Jeong Yee1
1Division of Life and Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University.
Abstract:
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.
Insights
Gefitinib-induced liver injury (hepatotoxicity) in non-small cell lung cancer patients is influenced by CYP3A4 inhibitors, smoking, and EGFR mutations. Stopping gefitinib significantly speeds up liver recovery.
Area of Science:
- Oncology
- Pharmacology
- Hepatology
Background:
- Gefitinib is an EGFR tyrosine kinase inhibitor for non-small cell lung cancer (NSCLC) with EGFR mutations.
- Gefitinib-induced hepatotoxicity is a known adverse event, but factors influencing its onset and recovery time are not well understood.
Purpose of the Study:
- To investigate factors affecting the time to develop gefitinib-induced hepatotoxicity.
- To identify factors influencing the recovery time from gefitinib-induced hepatotoxicity.
Main Methods:
- Retrospective study of 473 NSCLC patients treated with gefitinib (January 2013 - December 2014).
- Data collected included patient demographics, clinical factors, gefitinib dose, EGFR mutation status, and concomitant medications.
- Multivariate models were used to analyze time to hepatotoxicity and recovery.
Main Results:
- Concomitant use of CYP3A4 inhibitors and smoking significantly shortened the time to hepatotoxicity (approximately 5-fold and 2-fold, respectively).
- EGFR exon 21 mutations prolonged the time to hepatotoxicity (about 2.4-fold), while exon 19 mutations increased hepatotoxicity risk (2-fold).
- Cessation of gefitinib therapy significantly accelerated recovery (3.8-fold faster).
Conclusions:
- CYP3A4 inhibitors, smoking, and EGFR exon 21 mutations are key factors influencing the onset of gefitinib-induced hepatotoxicity.
- Discontinuation of gefitinib is the primary factor that accelerates recovery from drug-induced liver injury.
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