title: 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.
abstract: 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.
authors.affiliation: Institute of Pharmacology, University of Aarhus, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Jakobsen
authors.forename: B
authors.initials: B
authors.lastname: Sørensen
authors.forename: L
authors.initials: L
authors.lastname: Bastholt
authors.forename: M R
authors.initials: MR
authors.lastname: Mirza
authors.forename: S B
authors.initials: SB
authors.lastname: Gjedde
authors.forename: H T
authors.initials: HT
authors.lastname: Mouridsen
authors.forename: C
authors.initials: C
authors.lastname: Rose
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000008:administration & dosage; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011929:Razoxane / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: D013629:Tamoxifen; D015251:Epirubicin; D011929:Razoxane; D003520:Cyclophosphamide; D005472:Fluorouracil