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Cancer Chemotherapy and Pharmacology

, Volume 42, Issue 5, pp 363–366 | Cite as

Pharmacokinetic analysis of high-dose toremifene in combination with doxorubicin

  • Gregory T. Wurz
  • Lin Soc
  • Vernon D. Emshoff
  • Timothy B. Cadman
  • Michael W. DeGregorio
ORIGINAL ARTICLE

Abstract

Purpose: Toremifene (Fareston) is an orally administered triphenylethylene derivative with chemosensitizing activity in vitro in estrogen receptor-negative multidrug-resistant human breast cancer cells. The purpose of this study was to evaluate the effects of high-dose toremifene (600 mg/day for 5 days) on the plasma pharmacokinetics of doxorubicin in humans. The 600-mg dose had been previously established as the maximum tolerated dose in a phase I study of 35 patients. Methods: Doxorubicin was administered as an intravenous (i.v.) bolus over 15 min at a dose of 60 mg/m2 to 11 patients in the absence of toremifene pretreatment to establish baseline doxorubicin pharmacokinetics. Six of these patients received 600 mg/day toremifene for 5 days 4 weeks later, followed by an i.v. bolus dose of doxorubicin (60 mg/m2) on day 5. During toremifene pretreatment, blood specimens (5 ml) were drawn at 0, 2, 4, and 24 h after dosing to assess peak levels. Following doxorubicin administration in each cycle, blood specimens were collected over a 72-h period for determination of the terminal half-life of elimination. Plasma concentrations of doxorubicin and toremifene were assessed by high-performance liquid chromatography (HPLC). Cumulative linear areas under the time-concentration curve (AUC) for doxorubicin were calculated using a noncompartmental model. Results: Prior to toremifene dosing, baseline doxorubicin pharmacokinetic studies showed an average terminal half-life of elimination of 40.04 ± 7.86 h in 4 patients, and an average AUC of 135 600 ± 67 600 μg/ml · h in 11 patients. In 4 of the patients receiving 600 mg/day toremifene for 5 days, the average terminal half-life of elimination was 38.12 ± 7.81 h, and the average AUC was 141 900 ± 62 900 μg/ml · h in 6 patients, i.e. a slight increase of 4.6%. No statistically significant change in the doxorubicin elimination kinetics with or without toremifene therapy was observed. Conclusions: Toremifene does not appear to interfere with the elimination kinetics of doxorubicin.

Key words Toremifene Doxorubicin MDR Drug interaction 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Gregory T. Wurz
    • 1
  • Lin Soc
    • 1
  • Vernon D. Emshoff
    • 1
  • Timothy B. Cadman
    • 1
  • Michael W. DeGregorio
    • 1
  1. 1.Department of Internal Medicine, Division of Hematology/Oncology, Cancer Center, University of California, Davis, 4501 X Street Room, 3016, Sacramento, California 95817, USA Tel.: +1-916-734-2360; Fax: +1-916-734-2374 E-mail: mwdegregorio@ucdavis.eduUS

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