Multiple-dose pharmacokinetics of epirubicin at four different dose levels: studies in patients with metastatic breast cancer

Summary

Pharmacokinetic analysis of epirubicin and its metabolites epirubicinol and 7-deoxy-13-dihydro-epirubicinol aglycone during the first and the fourth courses of treatment was performed in 78 patients with metastatic breast cancer. The patients were treated every 3 weeks with epirubicin given as 10-min i.v. infusions at four different dose levels: 40, 60, 90 and 135 mg/m². In most cases (76 of 78 cases), plasma concentration-time curves fitted to a three-compartmental pharmacokinetic model. The terminal half-life of epirubicin was independent of dose and duration of treatment. Large interindividual differences were demonstrated (meant _1/2γ, 21.6±7.9 h; range, 10.6–69 h;n=110). In two subjects, extremely long half-lives and high serum bilirubin concentrations indicated impaired liver function. No correlation was found between the half-life and levels of liver alanine aminotransferase (ALAT) or serum creatinine. The metabolite epirubicinol appeared quickly after epirubicin administration and its half-lives were shorter than that of the parent compound (meant _1/2γ, 18.1±4.8 h; range, 8.2–38.4 h;n=105).Formation of the aglycone metabolite was delayed and the half-life of this metabolite was shorter than that of epirubicin (meant _1/2γ, 13±4.6 h; range, 2.7–29 h;n=104). The AUC of epirubicin and the total AUC (drug and metabolites) were linearly proportional to the dose, with the former value constituting two-thirds of the latter. A correlation was found between AUC and the plasma concentration of epirubicin at two time points (2 and 24 h after administration). The proposed model was AUC=9.44×c ₂+62.5×c ₂₄+157.7 (r=0.953).