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Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia

Leukemia volume 16, pages 920–927 (2002)Cite this article

Abstract

The purpose of this study was to assess the effect of the multidrug resistance modulator cyclosporine (CsA) on the pharmacokinetics of etoposide and mitoxantrone in children with de novo acute myeloid leukemia (AML). Serial blood samples for pharmacokinetic studies were obtained in 38 children over a 24-h period following cytotoxin treatment with or without CsA on days 1 and 4. Drug concentrations were quantitated using validated HPLC methods, and pharmacokinetic parameters were determined using compartmental modeling with an iterative two-stage approach, implemented on ADAPT II software. Etoposide displayed a greater degree of interindividual variability in clearance and systemic exposure than mitoxantrone. With CsA treatment, etoposide and mitoxantrone mean clearance declined by 71% and 42%, respectively. These effects on clearance, in combination with the empiric 40% dose reduction for either cytotoxin, resulted in a 47% and 12% increases in the mean AUC for etoposide and mitoxantrone, respectively. There were no differences in the rates of stomatitis or infection between the two groups. CsA treatment resulted in an increased incidence of hyperbilrubinemia, which rapidly reversed upon conclusion of drug therapy. The variability observed in clearance, combined with the empiric 40% dose reduction of the cytotoxins, resulted in statistically similar systemic exposure and similar toxicity.

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Acknowledgements

This study was supported in part by NIH grants R01 CA 52168 (BIS) and M01 RR 00070 (General Clinical Research Center, Stanford University School of Medicine). Dr Lacayo is supported by a Clinical Associate Physician award from the General Clinical Research Centers (M01 RR 00070), and was a recipient of a Clinical Development Award from the American Society of Clinical Oncology. The Pediatric Oncology Group and its member institutions are supported by the following NIH grants: CA03161, CA69177, CA33587, CA29691, CA07431, CA28439, CA33625, CA41573, CA29293, CA15525, CA31566, CA20543, CA28473, CA33603, CA15898, CA11233, CA32053, CA69428, CA28383, CA25408, CA05587, CA30969, CA29139.

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Authors and Affiliations

  1. Divisions of Pediatric Hematology Oncology, Stanford University School of Medicine, Palo Alto, CA, USA

    NJ Lacayo & GV Dahl

  2. Division of Medical Oncology, Stanford University School of Medicine, Palo Alto, CA, USA

    BL Lum & BI Sikic

  3. Arkansas Children's Hospital, Little Rock, AR, USA

    DL Becton

  4. Massachusetts General Hospital, Boston, MA, USA

    H Weinstein

  5. Children's Hospital of Michigan, Detroit, MI, USA

    Y Ravindranath

  6. Pediatric Oncology Group Statistical Office at the University of Gainesville, FL, USA

    MN Chang

  7. Baylor College of Medicine, Houston, TX, USA

    L Bomgaars

  8. Emory University School of Medicine, Atlanta, GA, USA

    SJ Lauer

  9. Pediatric Oncology Group Operations Office, Chicago, IL, USA

    SJ Lauer

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  1. NJ Lacayo
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Correspondence to GV Dahl.

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Lacayo, N., Lum, B., Becton, D. et al. Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia. Leukemia 16, 920–927 (2002). https://doi.org/10.1038/sj.leu.2402455

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