Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity.

Dexrazoxane is a derivative of the powerful metal-chelating agent ethyl enediamine tetra acetic acid. Its cardioprotective effect is thought to be due to its ability to chelate iron and reduce the number of metal ions complexed with anthracycline and, consequently, decrease the formation of superoxide radicals. Preclinical studies have confirmed that dexrazoxane has significant activity as a cardioprotective agent against anthracycline-induced cardiotoxicity. Dexrazoxane is well-tolerated, with myelosuppression being the dose-limiting toxicity in Phase I trials. The cardioprotective utility of dexrazoxane has been further illustrated in a number of randomized trials. In addition no significant difference in survival has been observed between the dexrazoxane and control arms of these trials but, in one, a significantly lower response rate was observed in the dexrazoxane compared to placebo arm. Further trials are required to evaluate the efficacy of dexrazoxane in hematological malignancies as well as the adjuvant treatment of breast cancer. Its use in the paediatric setting and in the management of elderly patients with cardiac comorbidity also requires investigation. Recently, interest has focused on the use of dexrazoxane as an antidote for anthracycline extravasation. In addition the general cytoprotective activity of this drug requires further assessment, as well as selectivity in this context.

The pharmacokinetics of high-dose epirubicin and of the cardioprotector ADR-529 given together with cyclophosphamide, 5-fluorouracil, and tamoxifen in metastatic breast-cancer patients.

A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-microns silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600-1000 mg/m2) together with different doses of epirubicin (E, 60-100 mg/m2), fixed-dose cyclophosphamide (C, 600 mg/m2), fixed-dose 5-fluorouracil (F, 600 mg/m2), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m2. We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.