Cremophor Pharmacokinetics in Patients Receiving 3-, 6-, and 24-Hour Infusions of Paclitaxel

Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Australia.
JNCI Journal of the National Cancer Institute (Impact Factor: 12.58). 10/1996; 88(18):1297-301. DOI: 10.1093/jnci/88.18.1297
Source: PubMed


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 microL/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.
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.
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.
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 1 microL/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 1 microL/mL or more. The eight patients who achieved plasma Cremophor concentrations of 1 microL/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 microL/mL was 8.9 +/- 5.0 hours (mean +/- standard deviation; range, 4.1-15.6 hours). For the eight patients who achieved plasma Cremophor concentrations of 1 microL/mL during the 6-hour infusion, the total time that the concentration was greater than 1 microL/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 microL/mL or more only during the 3-hour infusion.
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.

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Available from: Lorraine Webster
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    • "Paclitaxel is a hydrophobic compound and is traditionally administered with castor oil so that it becomes solvent in aqueous media [Rischin et al. 1996]. A different approach is based on linking the active compound to albumin and forming albumin-based, hydrophilic nanoparticles [Di Costanzo et al. 2009]. "
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    • "The plasma concentration of polysorbate 80 is about 0.1% during the infusion and the compound is rapidly cleared from plasma [4,5]. This is in contrast to Cremophor EL, the solvent for paclitaxel, where about 27 ml is infused together with a standard dose (303 mg), and the plasma concentration remains high (above 0.1%) for days due to a low volume of distribution (3 L/m2) and a long half-life (40–80 h) [6-10]. Cremophor EL has been reported to have a negative influence on the reproducibility of paclitaxel determinations [11]. "
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    • "Information on the pharmacokinetics of Cremophor EL in patients is limited. A previous paper using a bio-assay reported Cremophor EL levels up to 0.2% (Webster et al, 1993; Rischin et al, 1996). However, our preliminary information using the HPLC assay has revealed that the Cremophor EL levels are much higher (Sparreboom et al, 1996b; Van Tellingen et al, 1996). "
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