caa a22 4500 397561768 CHVBK 20180308164817.0 cr unu---uuuuu 161202e19960918xx s 000 0 eng 10.1093/jnci/88.18.1297 doi (NATIONALLICENCE)oxford-10.1093/jnci/88.18.1297 Cremophor Pharmacokinetics in Patients Receiving 3-, 6-, and 24-Hour Infusions of Paclitaxel [Elektronische Daten] [Danny Rischin, Lorraine K. Webster, Michael J. Millward, Bernadette M. Linahan, Guy C. Toner, Anne M. Woollett, Carmel G. Morton, James F. Bishop] Background Paclitaxel (Taxol) is a new drug with efficacy against a variety of malignant tumors. The clinical formulation of paclitaxel contains 50% Cremophor EL, a polyethoxylated castor oil vehicle (carrier) that can reverse multidrug resistance (MDR) mediated by P-glycoprotein. Three-hour intravenous infusions of paclitaxel can yield end-of-infusion plasma Cremophor concentrations of 1 μL/mL or more, which are sufficient to reverse MDR in vitro by at least 50%. Despite extensive clinical use, the pharmacokinetics of Cremophor have not been described. Purpose We studied the pharmacokinetics of Cremophor in patients with ovarian cancer who were undergoing treatment with paclitaxel to determine whether plasma Cremophor concentrations achieved during and following 3-, 6-, and 24-hour 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 assigned to receive one 3-hour, one 6-hour, and one 24-hour infusion of paclitaxel in varied sequences during their first three cycles of treatment with this drug. Blood samples were collected both during and following the three infusion periods, and Cremophor concentrations in these samples were measured by use of a bioassay based on the ability of Cremophor in plasma samples to reverse cellular resistance to daunorubicin in vitro. Results Ten patients were treated with paclitaxel at a dose level of 175 mg/m2, and one patient was treated at a dose level of 135 mg/m2. At the 175-mg/m2 dose level, peak plasma Cremophor concentrations of 1μL/mL or more were achieved in eight of 10 patients during both the 3-hour and the 6-hour infusions; with the 24-hour infusion, only one patient achieved a peak plasma Cremophor concentration of 1μL/mL or more. The eight patients who achieved plasma Cremophor concentrations of 1 μL/mL during the 3-hour infusion were above this level 30 minutes into the infusion; the total time that the plasma concentration was greater than 1 μL/mL was 8.9 ± 5.0 hours (mean ± standard deviation; range, 4.1-5.6 hours). For the eight patients who achieved plasma Cremophor concentrations of 1 μL/mL during the 6-hour infusion, the total time that the concentration was greater than 1 μL/mL was 10.2 ± 9.0 hours (range, 0.3-21.9 hours). The patient who received paclitaxel at a dose of 135 mg/m2 achieved a peak plasma Cremophor concentration of 1 μL/mL or more only during the 3-hour infusion. Conclusions Paclitaxel infusions of 3 and 6 hours can result in sustained plasma Cremophor concentrations sufficient for substantial reversal of P-glycoprotein-mediated MDR in vitro. These plasma Cremophor concentrations are not achieved during 24-hour infusions of paclitaxel. [J Natl Cancer Inst 1996; 88: 1297-1301] © Oxford University Press REPORTS nationallicence Rischin Danny Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute Melbourne, Australia aut Webster Lorraine K. Trescowthick Research Laboratories, Peter MacCallum Cancer Institute Melbourne, Australia aut Millward Michael J. Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute Melbourne, Australia aut Linahan Bernadette M. Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute Melbourne, Australia aut Toner Guy C. Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute Melbourne, Australia aut Woollett Anne M. Division of Nursing, Peter MacCallum Cancer Institute Melbourne, Australia aut Morton Carmel G. Division of Nursing, Peter MacCallum Cancer Institute Melbourne, Australia aut Bishop James F. Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute Melbourne, Australia aut JNCI: Journal of the National Cancer Institute Oxford University Press 88/18(1996-09-18), 1297-1301 0027-8874 88:18<1297 1996 88 jnci https://doi.org/10.1093/jnci/88.18.1297 text/html Onlinezugriff via DOI 1 other jats NATIONALLICENCE 856 40 https://doi.org/10.1093/jnci/88.18.1297 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Rischin Danny Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute Melbourne, Australia aut NATIONALLICENCE 700 1- Webster Lorraine K. Trescowthick Research Laboratories, Peter MacCallum Cancer Institute Melbourne, Australia aut NATIONALLICENCE 700 1- Millward Michael J. Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute Melbourne, Australia aut NATIONALLICENCE 700 1- Linahan Bernadette M. Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute Melbourne, Australia aut NATIONALLICENCE 700 1- Toner Guy C. Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute Melbourne, Australia aut NATIONALLICENCE 700 1- Woollett Anne M. Division of Nursing, Peter MacCallum Cancer Institute Melbourne, Australia aut NATIONALLICENCE 700 1- Morton Carmel G. Division of Nursing, Peter MacCallum Cancer Institute Melbourne, Australia aut NATIONALLICENCE 700 1- Bishop James F. Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute Melbourne, Australia aut NATIONALLICENCE 773 0- JNCI: Journal of the National Cancer Institute Oxford University Press 88/18(1996-09-18), 1297-1301 0027-8874 88:18<1297 1996 88 jnci Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford