CLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS OF PACLITAXEL - A 3-HOUR INFUSION VERSUS A 24-HOUR INFUSION

The present study was conducted to compare the pharmacokinetics and ph armacodynamics (PD) of paclitaxel between Phase I trials of 3- and 24- h infusions and to determine the most informative pharmacokinetic para meter to describe the PD, Twenty-seven patients were treated in a Phas e I study of paclitaxel by a 3-h infusion at one of six doses: 105, 13 5, 180, 210, 240, and 270 mg/m(2). Pharmacokinetic data were obtained from all patients, Paclitaxel concentrations were measured in the plas ma and urine using HPLC. The pharmacokinetics and PD were compared wit h those of a Phase I trial of paclitaxel by a 24-h schedule previously performed, The maximum tolerated dose of paclitaxel by a 3-h infusion was determined to be 240 mg/m(2). The major toxicities were granulocy topenia, neuromuscular toxicities, and hypotension, Apparent differenc es in pharmacodynamic relationships for the change in granulocytes wit h dose, peak concentration, and areas under the concentration versus t ime curve were observed between the 3- and 24-h schedules, However, th e relationship between the duration of plasma concentration above 0.05 mu M and the change in granulocytes could be fitted to the same sigmo id maximum effect model in either schedule (P < 0.01), There were no c lear relationships between peripheral neuropathy or hypotension and an y pharmacokinetic parameters, The pharmacokinetics and PD of paclitaxe l were schedule dependent, The duration of plasma concentration above 0.05 mu M could be a common pharmacokinetic parameter predicting granu locytopenia for both schedules.