Comparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer

• Published in: Cancer chemotherapy and pharmacology 1990-01, Vol.25 (6), p.435-439
• Main Authors: BRONCHUD, M. H, MARGISON, J. M, HOWELL, A, LIND, M, LUCAS, S. B, WILKINSON, P. M
• Format: Article
• Language: English
• Subjects: Adult; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - blood; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Doxorubicin - metabolism; Doxorubicin - pharmacokinetics; Female; General aspects; Half-Life; Humans; Medical sciences; Metabolic Clearance Rate; Middle Aged; Naphthacenes - pharmacokinetics; Pharmacology. Drug treatments
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/BF00686055

Recombinant human granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenia following cytotoxic therapy, thereby enabling dose escalation to improve the response rate. It is important to know whether drug kinetics change as doses are increased. Doxorubicin was selected because of its broad spectrum of activity and its known efficacy in metastatic breast cancer. Doses of 75, 100, 125 and 150 mg/m2 were given to 11 patients with metastatic breast cancer by infusion over 30 min. Serum concentrations of parent drug and metabolites were determined during the first 48 h following the infusion by high-performance liquid chromatography (HPLC). The serum concentration vs time curve decayed as a triple exponential function in four patients and as a double exponential function in seven. A four-compartment model, one central and three peripheral, would predict concentrations to within 1 SE of the observed values. Doxorubicinol was the principal metabolite, and doxorubicinone and 7-deoxydoxorubicinone were clearly identified. There was a linear increase in the AUC infinity with dose. In addition, a small and transient increase in circulating levels of doxorubicinol and other important metabolites was observed 6 h following the administration of doxorubicin, which suggests the existence of an enterohepatic, or other, re-circulation mechanism. We conclude that in the dose range selected the kinetics of doxorubicin are linear and that the increase in toxicities seen with the higher doses of doxorubicin, following the second and third fortnightly administration, may be due to intracellular drug accumulation in tissues.