CREMOPHOR PHARMACOKINETICS IN PATIENTS RECEIVING 3-HOUR, 6-HOUR, AND 24-HOUR INFUSIONS OF PACLITAXEL

Background: Paclitaxel (Taxol) is a new drug with efficacy against a v ariety of malignant tumors, formulation of paclitaxel Cremophor EL, a polyethoxylated castor oil vehicle (carrier) that can reverse multidru g resistance (MDR) mediated by P-glycoprotein, Three-hour intravenous infusions of paclitaxel can yield end-of-infusion plasma Cremophor con centrations of 1 mu L/mL or more, which are sufficient to reverse MDR in vitro by at least 50%, Despite extensive clinical use, the pharmaco kinetics of Cremophor have not been described, Purpose: We studied the pharmacokinetics of Cremophor in patients with ovarian cancer who wer e undergoing treatment with paclitaxel to determine whether plasma Cre mophor concentrations achieved during and following 3-, 6-, and 24-hou r drug infusions were similar to those shown to modulate MDR in vitro, Methods: Eleven patients with previously treated (i,e,, with platinum -containing chemotherapy regimens) ovarian cancer were randomly assign ed to receive one 3-hour, one 6-hour, and one 24-hour infusion of pacl itaxel in varied sequences during their first three cycles of treatmen t with this drug, Blood samples were collected both during and followi ng the three infusion periods, and Cremophor concentrations in these s amples mere measured by use of a bioassay based on the ability of Crem ophor in plasma samples to reverse cellular resistance to daunorubicin in vitro, Results: Ten patients were treated with paclitaxel at a dos e level of 175 mg/m(2) and one patient was treated at a dose level of 135 mg/m(2), At the 175-mg/m(2) dose level, peak plasma Cremophor conc entrations of 1 mu L/mL or more were achieved in eight of 10 patients during both the 3-hour and the 6-hour infusions; with the 24-hour infu sion, only one patient achieved a peak plasma Cremophor concentration of I mu L/mL or more, The eight patients who achieved plasma Cremophor concentrations of 1 mu L/mL during the 3-hour infusion were above thi s level 30 minutes into the infusion; the total time that the plasma c oncentration was greater than 1 mu L/mL was 8.9 +/- 5.0 hours (mean +/ - standard deviation; range, 4.1-15.6 hours), For the eight patients w ho achieved plasma Cremophor concentrations of 1 mu L/mL during the 6- hour infusion, the total time that the concentration was greater than 1 mu L/mL was 10.2 +/- 9.0 hours (range, 0.3-21.9 hours), The patient who received paclitaxel at a dose of 135 mg/m(2) achieved a peak plasm a Cremophor concentration of 1 mu L/mL or more only during the 3-hour infusion, Conclusions: Paclitaxel infusions of 3 and 6 hours can resul t in sustained plasma Cremophor concentrations sufficient for substant ial reversal of P-glycoprotein-mediated MDR in vitro, These plasma Cre mophor concentrations are not achieved during 24-hour infusions of pac litaxel.