Assessment of ifosfamide pharmacokinetics, toxicity, and relation to CYP3A4 activity as measured by the erythromycin breath test in patients with sarcoma

Authors

  • Rashmi Chugh MD,

    1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan
    Search for more papers by this author
  • Thomas Wagner MD, PhD,

    1. Division of Hematology/Oncology, University of Lubeck, Lubeck Germany
    Search for more papers by this author
    • Dr. Wagner has acted as a consultant for Baxter Oncology.

  • Kent A. Griffith MPH, MS,

    1. Department of Biostatistics, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
    Search for more papers by this author
  • Jeremy M.G. Taylor PhD,

    1. Department of Biostatistics, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
    Search for more papers by this author
  • Dafydd G. Thomas MD, PhD,

    1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan
    Search for more papers by this author
  • Francis P. Worden MD,

    1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan
    Search for more papers by this author
  • Kirsten M. Leu MD,

    1. Oncology Hematology West, PC, Omaha, Nebraska
    Search for more papers by this author
  • Mark M. Zalupski MD,

    1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan
    Search for more papers by this author
  • Laurence H. Baker DO

    Corresponding author
    1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan
    • 24 Frank Lloyd Wright Drive, PO Box 483, Ann Arbor, MI 48106
    Search for more papers by this author
    • Dr. Baker has received grant support from Abbott, Aventis (Sanofi), Lilly, the National Institutes of Health, the Robert Urich Foundation, the Southwest Oncology Group, the Walther Foundation, and the Hyatt Corporation and is a member of the Advisory Boards of Ascenta, the Hope Foundation (Vice President), Kanisa, the NCCN Guidelines Committee, and SARC (Executive Director and Board Member).

    • Fax: (734) 998-7118


  • Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, Florida, May 19, 2002; the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, Illinois, June 2, 2003; and the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, Florida, May 13–17, 2005.

Abstract

BACKGROUND.

Ifosfamide is a chemotherapeutic agent that requires cytochrome P450 3A (CYP3A) for bioactivation and metabolism. To the authors' knowledge, the correlation between dose, pharmacokinetics, CYP3A, and toxicity has not been fully evaluated. A randomized Phase II trial was performed on 22 soft tissue sarcoma patients treated with doxorubicin (60 mg/m2/cycle) and either high-dose ifosfamide (12 g/m2/cycle) or standard-dose ifosfamide (6 g/m2/cycle). The pharmacokinetics of ifosfamide and CYP3A measurements observed are reported.

METHODS.

Pharmacokinetic parameters for ifosfamide, 2-dichloroethylifosfamide (2-DCE), and 3-dichloroethylifosfamide (3-DCE) were collected after the first ifosfamide infusion in 13 patients. Bayesian designed limited pharmacokinetic data were collected from an additional 41 patients. The erythromycin breath test (ERMBT) was performed on 81 patients as an in vivo phenotypic assessment of CYP3A activity.

RESULTS.

Fourteen-hour (peak) plasma levels of ifosfamide, 2-DCE, and 3-DCE were found to correlate strongly with the respective area under the curve (AUC) 0–24 values (r = 0.97, 0.94, and 0.95; P < .0001). Patients who experienced a grade 3–4 absolute neutrophil count (ANC), platelet, or creatinine toxicity (using the National Cancer Institute Common Toxicity Criteria [version 2]) were found to have statistically significantly higher median 14-hour plasma levels of ifosfamide, 2-DCE, and 3-DCE compared with patients with grade 0–2 toxicity. ERMBT was not found to correlate with pharmacokinetic parameters of ifosfamide and metabolites or toxicity.

CONCLUSIONS.

The 14-hour plasma level of ifosfamide, 2-DCE, and 3-DCE is a simple and appropriate substitute for describing the AUC of ifosfamide after 1 day of a 1‒hour to 2-hour infusion of drug. Fourteen-hour plasma levels of ifosfamide and metabolites are useful predictors of neutropenia, thrombocytopenia, and creatinine toxicity. ERMBT was not found to accurately correlate with ifosfamide pharmacokinetics or clinical toxicity. Cancer 2007. © 2007 American Cancer Society.

Ancillary