Multiple-dose pharmacokinetics of epirubicin at four different dose levels: studies in patients with metastatic breast cancer |
| |
Authors: | Preben Jakobsen Eva Steiness Lars Bastholt Mads Dalmark Anders Lorenzen Dorthe Petersen Susanne B Gjedde Erik Sandberg Carsten Rose Ole S Nielsen Henning T Mouridsen Anders Jakobsen |
| |
Institution: | (1) Department of Oncology, Odense University Hospital, Odense, Denmark;(2) Department of Oncology, Finsen Institute, Rigshospitalet, Copenhagen, Denmark;(3) Department of Oncology, Section of Clinical Research, Aarhus University Hospital, Aarhus, Denmark;(4) Department of Oncology, Esbjerg Hospital, Esbjerg, Denmark;(5) Institute of Pharmacology, University of Aarhus, The Bartholin Building, DK-8000 Aarhus, Denmark |
| |
Abstract: | 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
1/2 , 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
1/2 , 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
1/2 , 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).This work was supported by the Lundbeck Foundation, the Michaelsen Foundation and Farmitalia Carlo Erba Ltd. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|