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 e ffective in protection against anthracycline-induced cardiotoxicity, h as been developed. The limit of quantitation was 5 ng/ml using a narro w-bore 5-mu m 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/m(2)) together with different doses of epirubicin (E, 60-100 mg/m(2)), fixed -dose cyclophosphamide (C, 600 mg/m(2)), fixed-dose 5-fluorouracil (F, 600 mg/m(2)), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacok inetic 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 pharmacokin etics of epirubicin in the same combinations is altered with the admin istration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no sig nificant difference in epirubicin pharmacokinetic parameters when epir ubicin was given with or without concomitant administration of ADR-529 . Apart from minor changes in the distributional half-lives, the pharm acokinetic parameters of epirubicin were not altered with increasing d oses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 it self. Escalating doses of epirubicin did not significantly alter the p harmacokinetic parameters of ADR-529 with the exception of a 30% incre ase in the terminal half-life and a decrease in total body clearance w hen the epirubicin dose was raised from 60 to 100 mg/m(2). We conclude that concomitant administration of ADR-529 does not alter the distrib ution and elimination of epirubicin in doses suitable for preventing t he anthracycline-induced cardiotoxicity-