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 M 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 postmarketing 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 diseaserelated symptoms or incr...

Purpose: To describe the Food and Drug Administration (FDA) review and approval of sunitinib malate (Sutent). Sunitinib received regular approval for the treatment of gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate (Gleevec). Additionally, sunitinib received accelerated approval for the treatment of advanced renal cell carcinoma. Experimental Design: For the GIST indication, FDA reviewed data from a randomized, placebo-controlled trial with supportive evidence from a single-arm study. For the advanced renal cell carcinoma indication, FDA reviewed data from two single-arm studies of patients with cytokinerefractory metastatic renal cell carcinoma. Results: In patients with imatinib refractory or intolerant GIST, time-to-tumor progression of sunitinib-treated patients was superior to that of placebo-treated patients. Median time-to-tumor progression of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebotreated patients (P < 0.0001). Partial responses were observed in 6.8% of sunitinib-treated patients. In patients with metastatic renal cell carcinoma, partial responses were observed in 25.5% (95% confidence interval, 17.5, 34.9) and 36.5% (95% confidence interval, 24.7, 49.6) of patients treated with sunitinib. Median response durations were 27.1and 54 weeks. The most common adverse events attributed to sunitinib included diarrhea, mucositis, skin abnormalities, and altered taste. Reductions in left ventricular ejection fraction and severe hypertension were also more common in sunitinib-treated patients. Conclusions: On January 26, 2006, the FDA approved sunitinib for the treatment of patients with imatinib refractory or intolerant GIST. Accelerated approval was granted for the treatment of advanced renal cell carcinoma.

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP-based and transporter-based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA's current understanding of drug interactions (http://www.fda.gov/cder/drug/drugInteractions/default.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling.

The dose finding study of 54 patients showed a higher response rate for patients given 1.3 mg/m 2 compared with 1.0 mg/m 2 twice weekly for two of the 3-week schedule, but the study was too small for statistical dose-response comparisons. The most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness) in 65%, nausea (64%), diarrhea (51%), appetite decreased (including anorexia; 43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%, including peripheral sensory neuropathy and peripheral neuropathy aggravated), pyrexia (36%), vomiting (36%), and anemia (32%).Conclusions: The FDA granted marketing approval to Millennium Pharmaceuticals on May 13, 2003 for bortezomib for use as a single agent for the treatment of multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. Accelerated approval was based on a surrogate end point of response rate rather than clinical benefit, such as an improvement in survival. The recommended dose of bortezomib is 1.3 mg/m 2 administered twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). Accelerated approval was based on the results of two Phase II studies in a total of 256 patients and additional Phase I safety information. Mandated Phase IV study commitments to characterize clinical efficacy and safety more precisely are discussed.