A PHARMACOKINETIC AND PHARMACODYNAMIC STUDY OF THE NEW ANTHRACYCLINE PIRARUBICIN IN BREAST-CANCER PATIENTS

We evaluated the pharmacokinetics of pirarubicin during 16 courses of therapy in 4 patients suffering from breast cancer who were treated with an association of pirarubicin (30-60 mg/m2 according to the hematologic tolerance to the previous course, the first course being given at a dose of 40 mg/m2) and continuous infusions of 5-fluorouracil (750 mg/m2 daily for 5 days). Pirarubicin's pharmacokinetics and metabolism were linear within this dose range; the metabolites identified were pirarubicinol, doxorubicin and doxorubicinol (AUC ratios of metabolite/pirarubicin were 0.6, 0.64 and 0.57 respectively). Pirarubicin's decay from plasma followed a two-compartmental pattern, showing half-lives of 15.6 min and 16.6 h; the total plasma clearance of the drug was 140 l/h-1/m-2, and the total volume of distribution was 2,830 l/m2. A relationship was observed between some pharmacokinetic parameters and the toxic effects of the drug: the percentage of survival of granulocytes was significantly correlated with the AUC values for doxorubicin and doxorubicinol, whereas that of platelets was significantly correlated with the AUC values for pirarubicin and pirarubicinol. This is the first study to demonstrate a pharmacokinetic/pharmacodynamic relationship for pirarubicin.