Pharmacological study of paclitaxel duration of infusion combined with GFR-based carboplatin in the treatment of ovarian cancer

Abstract.

Purpose: To determine the effect on systemic pharmacology and clinical toxicity of dose and mode of administration of paclitaxel combined with carboplatin in the treatment of ovarian cancer. Patients and methods: A total of 18 patients were treated with a dose of carboplatin determined by GFR, to attain a target AUC of 6 or 7 mg/ml·min. The paclitaxel dose was 175 or 200 mg/m² administered over approximately 1 or 3 h. The duration of infusion was randomized, crossing over to the alternative treatment for the second course. Blood samples were analysed for carboplatin, paclitaxel and for the excipients of the paclitaxel formulation, ethanol and Cremophor. Results: Overall the three-weekly schedule of administration of the combination of carboplatin and paclitaxel was well tolerated. There were no clinical differences in the toxicities observed between courses where a 1-h infusion was used compared with those with a 3-h infusion. The target AUC of carboplatin was achieved (mean±SD 114±20% of target). Analysis of paclitaxel pharmacokinetics did not show a difference in the AUC or time above a pharmacological threshold for the two infusion durations. The peak concentration of paclitaxel obtained at the end of the infusion (9.1 vs 4.5 µg/ml), and the plasma ethanol concentration (40.0 vs 20.5 mg/dl) were higher following the shorter duration infusion. Peak concentrations of Cremophor were not different. Conclusion: The combination of paclitaxel at a dose of 175 mg/m² and carboplatin at a target AUC of 6–7 mg/ml·min can safely be administered every 3 weeks. Also, a 1-h infusion of paclitaxel has no acute clinical disadvantage over a 3-h infusion and these durations of administration are pharmacologically equivalent.