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Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity

Takayuki Takimoto1, Takashi Kijima, Yasushi Otani

  • 1Department of Internal Medicine, Toyonaka Municipal Hospital, Osaka, Japan. tkijima@imed3.med.osaka-u.ac.jp

Clinical Lung Cancer
|May 14, 2013
PubMed
Abstract

Insights

Genetic variations in CYP2D6 may contribute to gefitinib-induced liver damage, especially when combined with CYP3A4 inhibitors. Erlotinib offers a safer alternative for patients with reduced CYP2D6 activity experiencing gefitinib toxicity.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Drug Metabolism

Background:

  • Gefitinib causes severe hepatotoxicity in a significant portion of Japanese non-small-cell lung cancer (NSCLC) patients.
  • Gefitinib metabolism involves cytochrome P450 enzymes, including CYP2D6, suggesting a role for genetic variations.

Purpose of the Study:

  • To investigate the association between CYP2D6 gene polymorphisms and gefitinib-induced hepatotoxicity in NSCLC patients.
  • To explore the safety of erlotinib in patients with reduced CYP2D6 activity who experienced gefitinib toxicity.

Main Methods:

  • Analyzed CYP2D6 gene polymorphisms in 55 NSCLC patients with gefitinib-induced hepatotoxicity.
  • Compared genotype distribution with the healthy Japanese population and examined correlations with clinical factors.
  • Assessed gefitinib rechallenge and erlotinib switching in patients with specific CYP2D6 alleles.

Main Results:

  • CYP2D6 genotype distribution did not differ from the general population.
  • Alleles *5 and *10 did not correlate with initial hepatotoxicity onset or severity.
  • Hepatotoxicity recurred upon gefitinib rechallenge in patients with *5/*10 alleles when co-administered with CYP3A4 inhibitors (P = .029).
  • Erlotinib was safely tolerated by patients with *5/*10 alleles who previously experienced gefitinib toxicity (P = .024).

Conclusions:

  • Reduced CYP2D6 function may contribute to gefitinib-induced hepatotoxicity, particularly when CYP3A4 is inhibited.
  • Erlotinib appears to be a safe alternative for patients with decreased CYP2D6 activity who have experienced gefitinib-induced liver injury.
Keywords:
CYP2D6ErlotinibGefitinibHepatotoxicityPolymorphisms

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