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A pharmacokinetic and safety study of intravenous arsenic trioxide in adult cancer patients with renal impairment

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Abstract

Purpose

This study evaluated the pharmacokinetic and safety profiles of arsenic trioxide given twice per week in adult cancer patients with advanced malignancies and varying degrees of renal function.

Methods

Patients received intravenous arsenic trioxide 0.15 mg/kg twice weekly for 4 weeks, followed by a 2-week rest period. The pharmacokinetic profiles of the pharmacologically active arsenical species, arsenious acid (AsIII), and its metabolites, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), were evaluated during the first cycle for 72 h following doses on days 1 and 22. Safety assessments were made at each treatment visit.

Results

Twenty patients received an average of 11 doses. Compared with normal renal function, mild to severe renal impairment decreased urinary excretion of AsIII and increased exposure to MMAV and DMAV 1.4- to 8-fold after multiple dose administration. Only severe renal impairment substantially increased exposure to AsIII (AUC0–t increased by 18% after a single dose and 40% after multiple doses). The safety profile of arsenic trioxide after limited treatment on a twice-per-week schedule was comparable across all renal function groups.

Conclusion

Renal impairment did increase the systemic exposure to arsenic and its methylated metabolites following standard daily dosing of arsenic trioxide. The data from the limited number of patients with severe renal dysfunction did not suggest that severe renal impairment affected the safety profile of arsenic trioxide in cancer patients who received limited treatment with arsenic trioxide.

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Acknowledgments

The authors gratefully acknowledge the editorial support provided by Bridget O’Keeffe, PhD, and Helix Medical Communications LLC. This study was funded by Cephalon, Inc., Frazer, Pennsylvania with additional support from NIH Grant No. M01 RR-000080 (SR) and NIH Grant GCRC M01RR00750 (CS).

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Author notes

  1. Christopher J. Sweeney

    Present address: Dana Farber Cancer Institute, 44 Binney Street, Rm 1230, Boston, MA, 02115, USA

Authors and Affiliations

  1. Department of Medicine, Indiana University, 535 Barnhill Drive, Rm 473, Indianapolis, IN, 46202, USA

    Christopher J. Sweeney & Jennifer M. Porter

  2. Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA

    Chris Takimoto & Leslie Wood

  3. Cephalon, Inc, Frazer, PA, USA

    William G. Tracewell, Mona Darwish & Denise M. D’Andrea

  4. Case Comprehensive Cancer Center, University Hospitals Case Medical Center, Cleveland, OH, USA

    Scot C. Remick

Authors
  1. Christopher J. Sweeney
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  2. Chris Takimoto
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  3. Leslie Wood
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  4. Jennifer M. Porter
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  5. William G. Tracewell
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  6. Mona Darwish
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  7. Denise M. D’Andrea
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  8. Scot C. Remick
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Corresponding author

Correspondence to Christopher J. Sweeney.

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Sweeney, C.J., Takimoto, C., Wood, L. et al. A pharmacokinetic and safety study of intravenous arsenic trioxide in adult cancer patients with renal impairment. Cancer Chemother Pharmacol 66, 345–356 (2010). https://doi.org/10.1007/s00280-009-1169-4

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  • DOI: https://doi.org/10.1007/s00280-009-1169-4

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