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  • Title: Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug-drug interaction.
    Author: Motonaga M, Yamamoto N, Makino Y, Ando-Makihara R, Ohe Y, Takano M, Hayashi Y.
    Journal: Cancer Chemother Pharmacol; 2015 Oct; 76(4):713-21. PubMed ID: 26233803.
    Abstract:
    PURPOSE: Docetaxel and gefitinib play key roles in the treatment of non-small-cell lung cancer (NSCLC), and their combination could be of interest. Both drugs are mainly metabolized by CYP3A4, and drug-drug interactions are a major concern. This phase I dose-finding study was designed to assess the tolerability and drug-drug interactions in this combination using full pharmacokinetic (PK) samplings. METHODS: Docetaxel was intravenously administered on days 1 and 22 at a dose of 45 or 60 mg/m(2). Gefitinib (250 mg/day) was orally administrated starting on day 2. Ten PK samplings of docetaxel were performed on days 1 and 22. Seven PK samplings of gefitinib were performed on day 18 ± 3 and on day 22. RESULTS: Twelve patients with advanced or metastatic NSCLC were enrolled without considering EGFR mutation status. The major toxicity was neutropenia. Two patients withdrew from this study due to dose-limiting toxicities; however, the toxicity profiles in this combination were generally acceptable. The docetaxel AUC0-24 and C max did not differ whether administered alone or with gefitinib, and the geometric mean ratios (GMRs) of AUC0-24 and C max (co-administrated/administrated alone) were 0.95 (90 % CI 0.85-1.06) and 0.95 (90 % CI 0.85-1.05), respectively. Furthermore, the GMRs of the steady state gefitinib AUC0-24 and C max were 0.93 (90 % CI 0.84-1.03) and 0.98 (90 % CI 0.88-1.09), respectively. CONCLUSION: The tolerability of 60 mg/m(2) docetaxel with 250 mg/day gefitinib was confirmed, and we observed no drug-drug interaction in this combination.
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