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The EGFR belongs to the ERB family of receptor tyrosine kinases. The EGFR type 1 (ErbBl or HER1) is overexpressed in many common malignancies, and may be activated by autocrine loops in many others. A truncated version of the EGFR (EGFRvIII) that has lost a portion of the extracellular ligand-binding domain and is constitutively activated is found in a subset of patients with glioblastoma.

Gefitinib (iressa; 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy) quinazoline) was discovered by screening a library for compounds that inhibited EGFR tyrosine kinase activity. Gefitinib is a specific inhibitor of the EGFR tyrosine kinase that competitively inhibits ATP binding. Gefitinib is 100 times less potent against highly related tyrosine kinases such as HER2 (ErbB2/neu) and does not inhibit a variety of serine/threonine kinases. The predominant problem with the clinical use of gefitinib has been relatively low response rates. Levels of EGFR expression do not correlate with clinical responses; however, patients whose non-small cell lung tumors have point mutations in the EGFR respond dramatically to gefitinib, similar to imatinib response in GIST with KIT mutations (see above). Thus, primary resistance could result from tumors that are not uniquely dependent on EGFR activity for survival. Although target inhibition by gefitinib has been demonstrated in normal skin, it is possible that poor tumor penetration of the drug could lead to incomplete EGFR inhibition. Alternatively, drug efflux, unappreciated mutations that affect drug sensitivity, or a variety of other factors may mediate lack of responsiveness.

Following oral administration of gefitinib, peak plasma concentrations are achieved within 3-7 hours. Mean absolute bioavailability of the oral formulation is 59%. Exposure to gefitinib is not significantly altered by food; however, coadministration of drugs that cause sustained elevations in gastric pH to >5 reduce mean gefitinib AUC by 47%. Administration of gefitinib once daily results in two- to eightfold accumulation with steady-state achieved after 7-10 doses. At steady state, circulating plasma concentrations typically are maintained within a two- to threefold range over the 24-hour dosing interval. The mean terminal t1/2 is 41 hours.

Metabolism of gefitinib is predominantly via CYP3A4. The major metabolite in plasma is O-desmethyl gefitinib; it is 14 times less potent than gefitinib. Inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations. Coadministration with rifampin (a CYP3A4 inducer) reduced mean gefitinib AUC by 83%. Coadministration with itraconazole (a CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib. Elimination of gefitinib is primarily by metabolism and excretion in feces.

Gefitinib is approved for the treatment of patients with non-small cell lung cancer who have failed standard chemotherapy. single-agent responses in these heavily pretreated patients are in the 12-18% range. However, there is a subset of patients who respond dramatically to gefitinib and these are predominantly nonsmoking women with bronchoalveolar tumors. This subset of patients has EGFR mutations that render the EGFR hypersensitive to ligand and to gefitinib. Many of the same EGFR mutations are found in tumors from patients that respond to another small molecule EGFR inhibitor, erlotinib (tarceva). The recommended dose of gefitinib is one 250-mg tablet daily, taken with or without food.

The most common adverse drug reactions are diarrhea, rash, acne, pruritus, dry skin, nausea, vomiting, and anorexia. A higher rate of most of these adverse events is observed in patients treated with 500 mg/day of gefitinib as compared to treatment with 250 mg/day. Most adverse events are of mild-to-moderate grade. Less than 2% of patients have permanently discontinued therapy. Adverse drug reactions usually occur within the first month of therapy and generally are reversible. Asymptomatic increases in liver transaminases have been observed and periodic liver function testing should be performed. Interstitial lung disease, which may be acute in onset, has been observed uncommonly in patients receiving gefitinib, and some cases have been fatal. The overall frequency of interstitial lung disease is ~0.3% outside of Japan and ~2% in Japan.

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Anti Ageing And Skincare Made Easy

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