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

Purpose: To determine the effect on systemic pharmacology and clinical toxi city of dose and mode of administration of paclitaxel combined with carbopl atin in the treatment of ovarian cancer. Patients and methods: A total of 1 8 patients were treated with a dose of carboplatin determined by GFR, to at tain a target AUC of 6 or 7 mg/ml.min. The paclitaxel dose was 175 or 200 m g/m(2) administered over approximately I or 3 h. The duration of infusion w as randomized. crossing over to the alternative treatment for the second co urse. Blood samples were analysed for carboplatin, paclitaxel and for the e xcipients of the paclitaxel formulation, ethanol and Cremophor. Results: Ov erall the three-weekly schedule of administration of the combination of car boplatin and paclitaxel was well tolerated. There were no clinical differen ces in the toxicities observed between courses where a 1-h infusion was use d compared with those with a 3-h infusion. The target AUC of carboplatin wa s achieved (mean +/- SD 114 +/- 20% of target). Analysis of paclitaxel phar macokinetics did not show a difference in the AUC or time above a pharmacol ogical threshold for the two infusion durations. The peak concentration of paclitaxel obtained at the end of the infusion (9.1 vs 4.5 pg/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 diffe rent. Conclusion: The combination of paclitaxel at a dose of 175 mg/m(2) an d carboplatin at a target AUC of 6-7 mg/ml.min can safely be administered e very 3 weeks. Also, a 1-h infusion of paclitaxel has no acute clinical disa dvantage over a 3-h infusion and these durations of administration are phar macologically equivalent.