PHASE-I AND PHARMACOKINETIC STUDY OF PACLITAXEL BY 24-HOUR INTRAVENOUS-INFUSION

Paclitaxel, a new antitubular agent, appears to be one of the most pro mising single agents for the chemotherapy of various solid tumors. The primary objectives of this phase I study of paclitaxel using 24-h con tinuous intravenous infusions were to determine the maximum tolerated dose of paclitaxel administered by this schedule to Japanese patients with solid tumors and to evaluate the pharmacokinetics of paclitaxel. Eighteen patients received one of five doses of paclitaxel, 49.5, 75, 105, 135 or 180 mg/m(2). Premedication with diphenhydramine, dexametha sone, and ranitidine was used to prevent acute hypersensitivity reacti ons. Pharmacokinetic data were obtained from all 18 patients. Dose-lim iting toxicities observed at 180 mg/m(2) consisted of grade 4 granuloc ytopenia associated with grade 3 infection. No severe HSRs or cardiac toxicity were detected. Reversible toxicities observed included liver dysfunction, alopecia, peripheral neuropathy and myalgias. Pharmacokin etic studies performed using high-performance liquid chromatography de monstrated that plasma concentrations of paclitaxel increased during t he 24-h infusion and declined immediately upon cessation of the infusi on with a half life of 13.1-24.6 h (75-180 mg/m(2)). Less than 10% of paclitaxel was excreted in the urine within 72 h. The peak plasma conc entrations and the areas under the concentration-versus-time curves in creased linearly with the dose administered. Antitumor activity was ob served in one patient with pulmonary metastasis from pharyngeal cancer . Based on these studies a phase TI trial dose of 135 mg/m(2) administ ered over 24 h was chosen.