indication

For the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of either platinum-based or docetaxel chemotherapies.

pharmacology

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 cells and cancer cells.

mechanism of action

Gefitinib inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited; and malignant cells are inhibited. Gefitinib is the first selective inhibitor of the EGFR tyrosine kinase which is also referred to as Her1 or ErbB-1. EGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers. Overexpression leads to inappropriate activation of the apoptotic Ras signal transduction cascade, eventually leading to uncontrolled cell proliferation.

toxicity

The acute toxicity of gefitinib up to 500 mg in clinical studies has been low. In non-clinical studies, a single dose of 12,000 mg/m² (about 80 times the recommended clinical dose on a mg/m² basis) was lethal to rats. Half this dose caused no mortality in mice. Symptoms of overdose include diarrhea and skin rash.

biotransformation

Primarily hepatic via CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group.

absorption

Absorbed slowly after oral administration with mean bioavailability of 60%.

half life

48 hours

route of elimination

Elimination is by metabolism (primarily CYP3A4) and excretion in feces. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.

drug interactions

Acenocoumarol: Gefitinib may increase the anticoagulant effect of acenocoumarol.

Amobarbital: The CYP3A4 inducer, amobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.

Anisindione: Gefitinib may increase the anticoagulant effect of anisindione.

Aprobarbital: The CYP3A4 inducer, aprobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.

Butabarbital: The CYP3A4 inducer, butabarbital, may decrease the serum concentration and therapeutic effects of gefitinib.

Butalbital: The CYP3A4 inducer, butalbital, may decrease the serum concentration and therapeutic effects of gefitinib.

Butethal: The CYP3A4 inducer, butethal, may decrease the serum concentration and therapeutic effects of gefitinib.

Carbamazepine: The CYP3A4 inducer, carbamazepine, may decrease the serum concentration and therapeutic effects of gefitinib.

Clarithromycin: This CYP3A4 inhibitor increases levels/toxicity of gefitinib

Dicumarol: Gefitinib may increase the anticoagulant effect of dicumarol.

Dihydroquinidine barbiturate: The CYP3A4 inducer, dihydroquinidine barbiturate, may decrease the serum concentration and therapeutic effects of gefitinib.

Erythromycin: This CYP3A4 inhibitor increases levels/toxicity of gefitinib

Ethotoin: The CYP3A4 inducer, ethotoin, may decrease the serum concentration and therapeutic effects of gefitinib.

Fosphenytoin: The CYP3A4 inducer, fosphenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.

Heptabarbital: The CYP3A4 inducer, heptabarbital, may decrease the serum concentration and therapeutic effects of gefitinib.

Hexobarbital: The CYP3A4 inducer, hexobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.

Itraconazole: Itraconazole, a strong CYP3A4 inhibitor, may decrease the metabolism of gefitinib. Monitor for changes in the therapeutic and adverse effects of gefitinib if itraconazole is initiated, discontinued or dose changed.

Ketoconazole: This CYP3A4 inhibitor increases levels/toxicity of gefitinib

Mephenytoin: The CYP3A4 inducer, mephenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.

Methohexital: The CYP3A4 inducer, methohexital, may decrease the serum concentration and therapeutic effects of gefitinib.

Methylphenobarbital: The CYP3A4 inducer, methylphenobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.

Pentobarbital: The CYP3A4 inducer, pentobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.

Phenobarbital: The CYP3A4 inducer, phenobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.

Phenytoin: The CYP3A4 inducer, phenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.

Primidone: The CYP3A4 inducer, primidone, may decrease the serum concentration and therapeutic effects of gefitinib.

Quinidine barbiturate: The CYP3A4 inducer, quinidine barbiturate, may decrease the serum concentration and therapeutic effects of gefitinib.

Rifampin: Rifampin reduces levels and efficacy of gefitinib

Ritonavir: This CYP3A4 inhibitor increases levels/toxicity of gefitinib

Secobarbital: The CYP3A4 inducer, secobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.

St. John's Wort: The CYP3A4 inducer, St. John's Wort, may decrease the serum concentration and therapeutic effects of gefitinib.

Talbutal: The CYP3A4 inducer, talbutal, may decrease the serum concentration and therapeutic effects of gefitinib.

Telithromycin: Telithromycin may reduce clearance of Gefitinib. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Gefitinib if Telithromycin is initiated, discontinued or dose changed.

Topotecan: The BCRP/ABCG2 inhibitor, Gefitnib, may increase the bioavailability and serum concentration of oral Topotecan. Monitor for change in the therapeutic and adverse effects of Topotecan if Gefitinib is initiated, discontinued or dose changed.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of gefitinib by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of gefitinib if voriconazole is initiated, discontinued or dose changed.

Warfarin: Gefitinib may increase the anticoagulant effect of warfarin.