Linked Life Data

14977817

Source:http://linkedlifedata.com/resource/pubmed/id/14977817

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2004-2-23
pubmed:abstractText
On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine,N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C(22)H(24)ClFN(4)O(3). Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 microM or more, well within the IC(50) values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1078-0432
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
10
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1212-8
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:14977817-Adolescent, pubmed-meshheading:14977817-Adult, pubmed-meshheading:14977817-Aged, pubmed-meshheading:14977817-Carcinoma, Non-Small-Cell Lung, pubmed-meshheading:14977817-Clinical Trials as Topic, pubmed-meshheading:14977817-Drug Administration Schedule, pubmed-meshheading:14977817-Drug Approval, pubmed-meshheading:14977817-Female, pubmed-meshheading:14977817-Humans, pubmed-meshheading:14977817-Inhibitory Concentration 50, pubmed-meshheading:14977817-Lung Neoplasms, pubmed-meshheading:14977817-Male, pubmed-meshheading:14977817-Middle Aged, pubmed-meshheading:14977817-Models, Chemical, pubmed-meshheading:14977817-Quinazolines, pubmed-meshheading:14977817-Receptor, Epidermal Growth Factor, pubmed-meshheading:14977817-Treatment Outcome, pubmed-meshheading:14977817-United States, pubmed-meshheading:14977817-United States Food and Drug Administration
pubmed:year
2004
pubmed:articleTitle
United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets.
pubmed:affiliation
Division of Oncology Drug Products, Center for Drug Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland 20857, USA. cohenma@cder.fda.gov
pubmed:publicationType
Journal Article