Gefitinib is an oral targeted anticancer drug belonging to the class of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, primarily used in the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations; it was developed by AstraZeneca and approved in the early 2000s, initially receiving accelerated approval in Japan (2002) and later in other countries based on its ability to inhibit EGFR-driven tumor cell proliferation by blocking intracellular signaling pathways involved in cancer growth and survival.
BRAND NAMES
Gefitinib is a targeted anticancer drug marketed mainly under the brand name Iressa and used for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). It is manufactured by AstraZeneca, and is also available worldwide in several generic and alternative brands such as Geftinat, Gefticip, Gefitero, and Gefonib.
MECHANISM OF ACTION
Gefitinib targets the epidermal growth factor receptor (EGFR), which is present on normal and cancer cells and regulates cell growth and proliferation; in non-small cell lung cancer, activating EGFR mutations such as exon 19 deletions and exon 21 (L858R) promote tumor growth, survival, angiogenesis, and metastasis, and gefitinib works by reversibly inhibiting EGFR tyrosine kinase activity, blocking receptor autophosphorylation and downstream signaling, with greater affinity for these mutant forms than wild-type EGFR, and it also partially inhibits IGF- and PDGF-mediated signaling at therapeutic concentrations.
PHARMACOKINETICS
Absorption: Rapidly absorbed after oral administration with ~60% bioavailability; food has no significant effect, although gastric pH >5 may reduce absorption.
Distribution: Extensively distributed in the body with a large volume of distribution (indicating high tissue penetration); plasma protein binding is ~90%.
Metabolism: Primarily metabolized in the liver via CYP3A4, with minor contributions from CYP2D6 and CYP3A5; major metabolite is O-desmethyl gefitinib.
Excretion: Mainly eliminated in feces (~86%), with minimal renal excretion (<4–7%).
PHARMACODYNAMICS
Gefitinib is a selective, reversible inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase that blocks ATP binding to the intracellular domain of EGFR, preventing receptor autophosphorylation and downstream signaling pathways (such as MAPK, PI3K/AKT, and JAK/STAT), thereby inhibiting tumor cell proliferation, promoting apoptosis, and reducing angiogenesis, with greater activity against activating EGFR mutations like exon 19 deletions and L858R than against wild-type EGFR.
DOSAGE AND STRENGTH
Formulation: Oral tablets
Strength: 250 mg tablet
Usual dose: 250 mg once daily
Administration: Taken continuously with or without food
Duration: Continued until disease progression or unacceptable toxicity
Dose adjustment: May be required in cases of severe adverse effects or liver impairment
FOOD INTERACTIONS
Gefitinib has relatively few food interactions; food does not significantly affect its overall absorption, so it can be taken with or without meals, but drugs or conditions that increase gastric pH (such as antacids, proton pump inhibitors, or H2 blockers) may reduce its absorption and effectiveness.
DRUG INTERACTIONS
Gefitinib has important drug interactions mainly due to its metabolism via CYP3A4. Strong CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine, and St. John’s wort) can reduce its plasma levels and effectiveness, while strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir, and clarithromycin) may increase toxicity. Acid-reducing agents like proton pump inhibitors, H2 blockers, and antacids can decrease absorption by increasing gastric pH. Caution is also advised when used with drugs affecting liver function or other targeted anticancer therapies due to potential additive toxicity.
CONTRAINDICATIONS
Gefitinib is contraindicated in patients with known hypersensitivity to gefitinib or any of its components, and its use should be avoided in patients with severe liver impairment or those who have previously experienced severe drug-induced interstitial lung disease (ILD) or hypersensitivity reactions related to EGFR inhibitors.
SIDE EFFECTS
Gefitinib commonly causes side effects such as diarrhea, skin rash (acneiform eruption), dry skin, itching, and paronychia, along with less frequent effects including nausea, vomiting, loss of appetite, and fatigue; more serious but rare adverse effects include interstitial lung disease (which may be severe or fatal), hepatotoxicity with elevated liver enzymes, ocular disorders (such as dry eye or keratitis), and severe skin reactions.
OVERDOSE
Gefitinib overdose may lead to increased severity of its known toxic effects, including severe diarrhea, skin rash, nausea, vomiting, and elevated liver enzymes, with potential risk of serious hepatotoxicity and interstitial lung disease; there is no specific antidote, so management is supportive and may include symptomatic treatment, monitoring of liver function, and discontinuation of the drug.
TOXICITY
Gefitinib (Iressa) is an EGFR tyrosine kinase inhibitor used mainly in non-small cell lung cancer (NSCLC), with common side effects such as acneiform rash (42–94%), diarrhea (18–56%), and stomatitis; although generally well tolerated, it carries serious risks including interstitial lung disease (ILD) and pneumonitis (about 1–2% incidence) as well as liver dysfunction, and interestingly, the presence of skin toxicity has been associated with improved survival outcomes.
