Pharmacokinetic evaluation of gefitinib when administered with chemotherapy.
Gefitinib is a small-molecule agent specifically targeted to inhibit the epidermal growth factor receptor-tyrosine kinase (EGFR-TK). Tumor responses have been achieved with gefitinib treatment in large, randomized monotherapy trials. In preclinical studies, gefitinib has shown additive and even supra-additive antitumor effects when combined with different cytotoxic agents. In phase I clinical trials, gefitinib was found to be well tolerated, with clinical efficacy observed well below the maximum tolerated dose. The pharmacokinetics of gefitinib allow it to be administered as a once-daily oral tablet. Several phase I studies have investigated the safety of gefitinib at daily doses of 250 mg or 500 mg in combination with chemotherapy agents for first-line treatment of a variety of common solid tumors. The potential for drug interactions between gefitinib and cytotoxic agents was evaluated through pharmacokinetic assessments. A randomized, crossover study investigated the interaction of gefitinib and carboplatin/paclitaxel in the treatment of advanced non-small-cell lung cancer (NSCLC). A second trial with an open-label design studied the combination of gefitinib with cisplatin/gemcitabine in patients with a variety of solid tumors, including NSCLC. In both pilot studies, the addition of gefitinib to chemotherapy did not increase the exposure of any of the chemotherapy agents tested. However, increased exposure to gefitinib was seen with the carboplatin/paclitaxel regimen. The addition of gefitinib to these chemotherapy regimens was generally well tolerated, and there was no apparent increase in higher-grade toxicity. Additional trials are evaluating gefitinib treatment in combination with chemotherapy.
Hammond
Lisa A
LA
Institute for Drug Development, Cancer Therapy Research Center, San Antonio, TX, USA. lhammond@idd.org
D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D002986:Clinical Trials as Topic; D004347:Drug Interactions; D000077156:Gefitinib; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D011799:Quinazolines; D017239:Paclitaxel; D002945:Cisplatin; D000077156:Gefitinib