Multiple-dose pharmacokinetics of epirubicin at four different dose levels: studies in patients with metastatic breast cancer.
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 (mean t1/2 gamma, 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 (mean t1/2 gamma, 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 (mean t1/2 gamma, 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 x c2 + 62.5 x c24 + 157.7 (r = 0.953).
Jakobsen
P
P
Institute of Pharmacology, University of Aarhus, Denmark.
Steiness
E
E
Bastholt
L
L
Dalmark
M
M
Lorenzen
A
A
Petersen
D
D
Gjedde
S B
SB
Sandberg
E
E
Rose
C
C
Nielsen
O S
OS
D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D015251:Epirubicin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans
D015251:Epirubicin