PHARMACOKINETICS OF HIGH-DOSE DOXORUBICIN ADMINISTERED AS A 6-H INTRAVENOUS-INFUSION IN BREAST-CANCER PATIENTS

The purpose of our investigation was to evaluate the pharmacokinetic p rofile of doxorubicin administered by a new schedule. Nine non-pretrea ted young women with high risk breast cancer (mean age: 38, range: 23- 45) entered this trial and received, cyclophosphamide (600 mg/m(2) giv en as a 30-min infusion followed by doxorubicin (120 mg/m(2)) as a con tinuous infusion over 6 h. Chemotherapy was combined with hematopoieti c factor support (G-CSF or GM-CSF). Blood was sampled over the 0-54 h period and 14 cycles were studied for pharmacokinetics. Doxorubicin as well as its major metabolite doxorubicinol were assayed in plasma spe cimen by high performance liquid chromatography. Mean doxorubicin plas ma concentration peak was 42.6 ng/ml (standard deviation (SD): 13.3). The mean terminal half-lives were 32.6 h (SD: 22.0) and 39.2 h (SD: 21 .6) for doxorubicin and doxorubicinol, respectively. Mean areas under the plasma concentration-time curve (AUC) were 413 ng/h(-1) ml (SD: 10 3) and 1,707 ng/h(-1) ml (SD: 815) for doxorubicin and doxorubicinol r espectively. Consequently, the ratio of the AUC of doxorubicinol to th at of doxorubicin was high (mean: 4.1 (SD:1.6)) contrasting with previ ous studies reporting ratios less than 1 in patients with normal liver function. The systemic clearance of doxorubicin was 5.23 l/min/m(2) ( SD: 1.91). The inter- and intra-patient variability for AUC was low fo r both drugs. Hence the coefficients of variation were 24.6% for doxor ubicin, 26.2% for doxorubicinol (inter-individual variation) and less than 10% for both compounds (intra-individual variation). In conclusio n, the pharmacokinetic profile of doxorubicin (120 mg/m(2)) administer ed as a 6 h-continuous infusion is characterized by a greater exposure to doxorubicinol. This could be explained by a saturation in the bili ary excretion process during the period following the end of the infus ion.