}

Gefitinib

Chemotherapies

Drug Overview

Gefitinib (brand name Iressa) is an oral targeted therapy belonging to the class of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. It is designed to interfere with cell signaling pathways that promote cancer cell proliferation.

Gefitinib is primarily indicated for the treatment of non–small cell lung cancer (NSCLC) in patients whose tumors have activating EGFR mutations. It helps to slow or stop tumor growth and can improve progression-free survival.

Mechanistically, gefitinib binds to the ATP‐binding site of the EGFR tyrosine kinase domain, blocking downstream signaling cascades involved in cell division and survival.

Relevant Genes and Their Roles

CYP2D6 is a liver enzyme that metabolizes many drugs, including gefitinib, through oxidative reactions. It helps convert gefitinib into more water-soluble forms for elimination. Genetic variants in CYP2D6 can alter the enzyme’s metabolic activity.

When CYP2D6 function is reduced, the body clears gefitinib more slowly, leading to higher drug levels. Conversely, increased CYP2D6 activity can lower drug exposure. Understanding these variations can help predict response and risk of side effects.

Impact of Genetics on Drug Response

Individuals with different CYP2D6 metabolizer phenotypes—ultrarapid, normal, intermediate or poor—can have significantly different gefitinib plasma levels. Poor metabolizers may accumulate higher drug concentrations, increasing toxicity risk, while ultrarapid metabolizers may clear the drug too quickly, potentially reducing efficacy.

Expected Clinical Effects of Genetic Variation

Ultrarapid Metabolizer

  • Effect on drug levels: Lower than average exposure due to rapid clearance
  • Clinical consequence: Potential reduced efficacy of gefitinib
  • Side effects: Generally fewer and milder adverse effects; infrequent occurrence

Normal Metabolizer

  • Effect on drug levels: Expected standard exposure
  • Clinical consequence: Typical therapeutic response
  • Side effects: As reported in clinical trials; moderate frequency and severity

Intermediate Metabolizer

  • Effect on drug levels: Slightly increased exposure compared to normal
  • Clinical consequence: Possible mild increase in efficacy and toxicity
  • Side effects: Mild adverse reactions; monitor frequency

Poor Metabolizer

  • Effect on drug levels: Higher than average exposure due to reduced clearance
  • Clinical consequence: Increased risk of toxicity and adverse reactions
  • Side effects: More frequent and severe side effects; close monitoring required

Indeterminate/Not Available

  • Effect on drug levels: Unknown
  • Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring
  • Side effects: Unknown; monitor patient as per usual clinical practice

Dosing Guidelines

The following dosing guidelines are based on the available guidelines for gefitinib metabolism by CYP2D6.

CYP2D6 Dosing Guideline

Phenotype Clinical Consequence Guideline Recommendation
Ultrarapid Metabolizer Likely lower drug exposure; potential reduced efficacy Use standard gefitinib dosing; no adjustment needed
Normal Metabolizer Expected standard exposure and response Use standard gefitinib dosing
Intermediate Metabolizer Slightly increased exposure; monitor for toxicity Use standard dosing; monitor for adverse reactions
Poor Metabolizer Increased exposure and risk of toxicity Monitor closely for adverse reactions; consider dose reduction if toxicity occurs
Indeterminate / Not available Unknown impact Initiate standard starting dose

Alternative Treatment Options

Examples of alternative EGFR-targeted therapies include erlotinib (Tarceva), afatinib (Gilotrif), and osimertinib (Tagrisso). These are provided as examples and do not constitute medical advice.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

Interested in learning more about how your genetics may affect your response to medication? Get started with Gene2Rx today.

I'm Interested