Interaction pharmacokinetis of pegylated liposomal doxorubicin (Caelyx) on coadministration with paclitaxel or docetaxel

Abstract

Purpose: To investigate the pharmacokinetics of polyethylene glycol-coated liposomal doxorubicin (PLD, Caelyx) when given as a single agent and in combination with the taxanes paclitaxel or docetaxel in humans. Methods: The plasma kinetics of PLD were studied in 19 cancer patients treated with PLD every 4 weeks combined with either paclitaxel (on a weekly basis in seven and as a single infusion in three patients) or docetaxel (weekly in seven and as a single infusion in two). Plasma concentrations of PLD were quantified in two sets of samples per patient to compare the same pharmacokinetic parameters in each subject when treated with single-agent PLD and again with the combination. Total doxorubicin concentrations in plasma were quantified by HPLC. Pharmacokinetics were evaluated by noncompartmental analysis and the data obtained were compared for differences by a matched-pairs nonparametric test. Results: Coadministration of paclitaxel produced a median/mean 54/80% increase in PLD AUCinf (95% confidence interval 23% to 136%, P=0.002). The observed increase was consistent among all subjects. PLD clearance was also decelerated in the presence of paclitaxel (P=0.013) while other pharmacokinetic parameters were affected modestly. A small increase in the AUC of PLD was observed in the docetaxel/PLD arm (mean increase 12%, P=0.039) while PLD clearance decreased marginally and other pharmacokinetic parameters remained unaffected. AUC extrapolated to infinity was below 8% in both arms. Conclusions: This study showed the presence of a pharmacokinetic interaction that led to higher plasma concentrations of PLD when combined with paclitaxel and to a minor extent when combined with docetaxel. This pharmacokinetic information may be of value when planning combination therapies of PLD with taxanes. © Springer-Verlag 2004.