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Pharmacokinetics of decitabine administered as a 3-h infusion to patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

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Abstract

Purpose

In this study, pharmacokinetics (PK) of decitabine administered as a 3-h intravenous infusion of 15 mg/m2 every 8 h for 3 days (cycles repeated every 6 weeks) was evaluated in patients with MDS or AML.

Methods

The PK of this dosing regimen was evaluated in sixteen patients with MDS or AML. Plasma samples were obtained pre-dose and during the first 8-h dosing interval on each dosing day during Cycle 1, and at pre-dose and just prior to the end of infusion during Cycle 2. PK samples were assayed for decitabine by a sensitive and specific validated liquid chromatography-tandem mass spectrometry method.

Results

The mean maximum observed plasma concentration (C max), 64.8–77.0 ng/ml, and the mean area under the plasma concentration-time curve (AUC0-∞), 152–163 ng h/ml, were unchanged during dosing of decitabine for 3 days. The time to the maximum concentration (T max) generally occurred at the end of infusion. The mean values for terminal phase elimination half-life (0.62–0.78 h), total body clearance (125–132 l/h per m2), and volume of distribution at steady state (62.7–89.2 l/m2), remained unchanged during the every 8 h dosing (P > 0.05). Cycles 1 and 2 C max values for days 1, 2, and 3 were not significantly different as determined by paired two-tailed t test (P > 0.05). The primary toxicity of decitabine was myelosuppression, which was observed in all patients. Two deaths, from sepsis, were considered possibly related to decitabine.

Conclusions

Decitabine dosed at 15 mg/m2 iv every 8 h for 3 days resulted in a predictable and manageable toxicity profile in patients with MDS/AML. The repeated dosing did not result in systemic accumulation of the drug, and decitabine PK remained unchanged from cycle to cycle.

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Authors and Affiliations

  1. Department of Medicine, Division of Bone Marrow Transplantation and Stem Cell Biology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8007, St. Louis, MO, 63110, USA

    Amanda F. Cashen, Laura Todt, Nicholas Fisher & John DiPersio

  2. MGI PHARMA, Inc., Bloomington, MN, USA

    Ajit K. Shah

Authors
  1. Amanda F. Cashen
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  2. Ajit K. Shah
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  3. Laura Todt
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  4. Nicholas Fisher
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  5. John DiPersio
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Correspondence to Amanda F. Cashen.

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Cashen, A.F., Shah, A.K., Todt, L. et al. Pharmacokinetics of decitabine administered as a 3-h infusion to patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Cancer Chemother Pharmacol 61, 759–766 (2008). https://doi.org/10.1007/s00280-007-0531-7

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  • DOI: https://doi.org/10.1007/s00280-007-0531-7

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