Comparative open, randomized, cross-over bioequivalence study of two intravenous dexrazoxane formulations (Cardioxane (R) and ICRF-187) in patients with advanced breast cancer, treated with 5-fluorouracil-doxorubicin-cyclophosphamide (FDC)

The purpose of this study was to compare the pharmacokinetic disposition of two intravenous dexrazoxane formulations, and their effects on doxorubicin 's kinetics and metabolism. Plasma concentration versus time curves and pha rmacokinetic parameters of dexrazoxane given as Cardioxane(R) (dexrazoxane hydrochloride salt) and ICRF-187 reference formulation (dexrazoxane base) w ere determined and compared. Both formulations were administered as a singl e intravenous infusion prior to 5-fluorouracil-doxorubicin-cyclophosphamide administration. In addition, the pharmacokinetics of doxorubicin and its m etabolites were studied after dexrazoxane administration. A total of 15 patients with advanced breast cancer participated in this ope n, randomized, cross-over study and 12 patients were evaluable. Plasma conc entrations of dexrazoxane, doxorubicin and doxorubicin metabolites were det ermined by high-performance liquid chromatography in samples obtained in th e 72 h after drug administration. No statistically significant differences were found in the tested kinetic parameters when the two products were comp ared by analysis of variance (ANOVA) on log-transformed data. Cardioxane(R) fulfilled the bioequivalence criteria when compared with ICRF-187 referenc e formulation for all of the investigated parameters (AUC, t(1/2 beta), V-d ss, Cl-tot, Cl-ren). The parametric 90% confidence intervals were contained within the bioequivalence interval (0.8-1.25). Pharmacokinetic parameters and metabolism of doxorubicin were not different after the administration o f either Cardioxane(R) or ICRF-187 formulation. From the results of this st udy it can be concluded that the two formulations can be considered bioequi valent with regard to extent of absorption (AUC and V-dss) and elimination (t(1/2 beta), and Cl-ren).