The mechanism of the clinical antitumor action of Gefitinib is not fully characterized. Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal and cancerous cells.

Gefitinib is slowly absorbed after oral administration, with a mean bioavailability of 60%. It is eliminated primarily through metabolism (mainly via CYP3A4) and excretion in the feces. The elimination half-life is approximately 48 hours. Daily oral administration of Gefitinib to cancer patients results in a two-fold accumulation compared to a single-dose administration. Steady-state plasma concentrations are achieved within 10 days.

Absorption and Distribution

Gefitinib is slowly absorbed, with peak plasma levels occurring 3–7 hours after dosing and a mean oral bioavailability of 60%. Food intake does not significantly alter bioavailability. Gefitinib is extensively distributed throughout the body, with a mean steady-state volume of distribution of 1,400 L following intravenous administration. In vitro binding of Gefitinib to human plasma proteins (serum albumin and α1-acid glycoprotein) is 90% and remains independent of drug concentrations.

Metabolism and Elimination

Gefitinib undergoes extensive hepatic metabolism, predominantly by CYP3A4. Three primary metabolic pathways have been identified:

Metabolism of the N-propoxymorpholino group

Demethylation of the methoxy-substituent on the quinazoline

Oxidative defluorination of the halogenated phenyl group

Five metabolites have been identified in human plasma, with only O-desmethyl Gefitinib exhibiting comparable exposure levels to Gefitinib. Although this metabolite shows similar EGFR-TK activity in isolated enzyme assays, it demonstrates only 1/14th of the potency of Gefitinib in cell-based assays.

Gefitinib is primarily cleared by the liver, with total plasma clearance and elimination half-life values of 595 mL/min and 48 hours, respectively, after intravenous administration. Excretion occurs predominantly via the feces (86%), while renal elimination accounts for less than 4% of the administered dose.

Gefitinib is indicated as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel chemotherapies. Its effectiveness is based on objective response rates.

The recommended daily dose of Gefitinib is one 250 mg tablet, which can be taken with or without food. Higher doses do not improve treatment response but can increase toxicity.

Dosage Modifications

Gefitinib should be withheld for up to 14 days in cases of:

Acute onset or worsening pulmonary symptoms (dyspnea, cough, fever)
≥ Grade 2 ALT and/or AST elevations
≥ Grade 3 diarrhea
Signs and symptoms of severe or worsening ocular disorders, including keratitis
≥ Grade 3 skin reactions

Gefitinib treatment may resume once adverse effects fully resolve or improve to Grade 1.

Permanent Discontinuation

Gefitinib should be permanently discontinued in cases of:

Confirmed interstitial lung disease (ILD)
Severe hepatic impairment
Gastrointestinal perforation
Persistent ulcerative keratitis
Co-administration with Strong CYP3A4 Inducers

If co-administered with strong CYP3A4 inducers, the dose may be increased to 500 mg once daily, provided no severe adverse drug reactions occur. Once the CYP3A4 inducer is discontinued, the 250 mg once-daily dose should be resumed.

Gefitinib is contraindicated in patients with severe hypersensitivity to Gefitinib or any of its components.

Pulmonary Toxicity

Cases of interstitial lung disease (ILD) have been reported in approximately 1% of patients receiving Gefitinib. Symptoms include interstitial pneumonia, pneumonitis, and alveolitis. Patients may experience an acute onset of dyspnea, sometimes associated with cough or low-grade fever, which can rapidly progress to severe respiratory distress requiring hospitalization.

Hepatotoxicity

Asymptomatic liver transaminase elevations have been observed in patients treated with Gefitinib. Therefore, periodic liver function testing (ALT, AST, bilirubin, and alkaline phosphatase) should be considered. Discontinuation should be considered in cases of severe hepatic impairment.

Patients should seek immediate medical attention if they experience:

Severe or persistent diarrhea, nausea, anorexia, or vomiting, as these symptoms may lead to dehydration.

New or worsening pulmonary symptoms, such as shortness of breath or persistent cough.

Eye irritation or vision changes.

Any other unusual or concerning symptoms.

The most common adverse effects associated with 250 mg daily dosing include:

Diarrhea
Skin rash, acne, dry skin
Nausea and vomiting

A higher dose (500 mg) has been associated with an increased incidence and severity of these adverse effects.

Pregnancy Category D

Gefitinib may cause fetal harm when administered to a pregnant woman. In animal studies, Gefitinib was found to cross the placenta, potentially leading to fetal toxicity.

There are no adequate and well-controlled studies in pregnant women. If a patient becomes pregnant while receiving Gefitinib, she should be informed about the potential risks to the fetus or pregnancy loss.

Use in Nursing Mothers

It is unknown whether Gefitinib is excreted in human milk. Due to the potential risks, breastfeeding should be discontinued while on Gefitinib therapy.

Pediatric Use: The safety and efficacy of Gefitinib in children have not been established.

Geriatric Use: Clinical trials have shown no significant differences in safety or efficacy between younger and older patients.

Severe Renal Impairment: The effects of severe renal impairment on Gefitinib pharmacokinetics are not well understood. Patients with severe renal impairment should be treated with caution.

The acute toxicity of Gefitinib at doses up to 500 mg in clinical studies has been low. In Phase 1 trials, some patients received doses up to 1,000 mg daily, resulting in increased severity of diarrhea and skin rash. Overdose management is symptomatic, with particular attention to severe diarrhea.

Store at a temperature not exceeding 30°C.

Keep in a dry place, protected from light and moisture.