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High single dose of mitoxantrone and cytarabine in acute non-lymphocytic leukemia: a pharmacokinetic and clinical study.

Abstract
In a phase I-II study, the authors evaluated the intracellular pharmacokinetics, toxicity, and efficiency of a high dose of mitoxantrone given as first induction in acute non-lymphocytic leukemia. Twenty-two patients with previously untreated de novo ANLL were included and received 30 or 40 mg/m2 mitoxantrone on day 1 by intravenous infusion over 1 hour and 500 mg/m2 ara-C twice a day for 5 days. If there was no complete remission (CR), a second induction with ara-C, etoposide, and amsacrine was given. The CR rate after two courses with this regimen was 77%. Median duration of severe neutropenia was 18 days in the 30-mg/m2 group and 25 days in the 40-mg/m2 group. Two patients had fatal lung complications probably unrelated to mitoxantrone. A third patient had a possible mitoxantrone-induced reversible lung complication. In the leukemic cells, we found a high accumulation of mitoxantrone which, in contrast to the plasma concentration, remained stable during the 48 hours studied. Compared with previous results with 12 mg/m2 mitoxantrone, the AUC for intracellular concentrations versus time for the first 20 hours studied was increased by 150% to 0.638 nmol/mg cell protein x hour with 30 mg/m2 mitoxantrone and by 260% to 1.103 nmol/mg cell protein x hour with 40 mg/m2 mitoxantrone. In conclusion, a high dose of mitoxantrone results in a high intracellular exposure of the leukemic cells, which may be an advantage in improving survival of these patients.
AuthorsL Möllgård, U Tidefelt, B Sundman-Engberg, C Löfgren, S Lehman, C Paul
JournalTherapeutic drug monitoring (Ther Drug Monit) Vol. 20 Issue 6 Pg. 640-5 (Dec 1998) ISSN: 0163-4356 [Print] United States
PMID9853980 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amsacrine
  • Cytarabine
  • Etoposide
  • Mitoxantrone
Topics
  • Adult
  • Aged
  • Amsacrine (pharmacology)
  • Chromatography, High Pressure Liquid
  • Cytarabine (administration & dosage, blood, pharmacology)
  • Drug Administration Schedule
  • Etoposide (pharmacology)
  • Female
  • Humans
  • Injections, Intravenous
  • Leukemia, Myeloid, Acute (drug therapy, metabolism, mortality)
  • Male
  • Middle Aged
  • Mitoxantrone (administration & dosage, blood, pharmacology)
  • Neutropenia (chemically induced)
  • Time Factors

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