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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

  • Original Article
  • Pharmacokinetics, ADR-529, Epirubicin, Metastatic Breast Cancer, High-Pressure Liquid Chromatography
  • Published:
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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-μm 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.

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Authors and Affiliations

  1. Institute of Pharmacology, University of Aarhus, The Bartholin Building, DK-8000, Aarhus, Denmark

    Preben Jakobsen

  2. Department of Oncology, Odense University Hospital, Odense, Denmark

    Bente Søresen, Lars Bastholt, Mansoor Raza Mirza & Carsten Rose

  3. Department of Oncology, Rigshospitalet, Copenhagen, Denmark

    Susanne B. Gjedde & Henning T. Mouridsen

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  1. Preben Jakobsen
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  2. Bente Søresen
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  3. Lars Bastholt
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  4. Mansoor Raza Mirza
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  5. Susanne B. Gjedde
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  6. Henning T. Mouridsen
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  7. Carsten Rose
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Jakobsen, P., Søresen, B., Bastholt, L. et al. 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. Cancer Chemother. Pharmacol. 35, 45–52 (1994). https://doi.org/10.1007/BF00686283

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  • DOI: https://doi.org/10.1007/BF00686283

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