Investigational New Drugs

, Volume 11, Issue 2–3, pp 187–195 | Cite as

Phase I clinical and pharmacokinetic trial of dextran conjugated doxorubicin (AD-70, DOX-OXD)

  • Susanne Danhauser-Riedl
  • Edith Hausmann
  • Hans-D. Schick
  • Rita Bender
  • Hermann Dietzfelbinger
  • Johann Rastetter
  • Axel-R. Hanauske
Phase I Studies

Abstract

Coupling of anthracyclines to high-molecular-weight carriers may alter drug disposition and improve antitumor effects. We have performed a clinical phase I trial of doxorubicin coupled to dextran (70000 m.w.). The drug was administered as single dose i.v. every 21–28 days. Thirteen patients have received a total of 24 courses (median 2; range 1–3). At the starting dose of 40 mg/m2 doxorubicin equivalent (DOXeq), WHO grade IV thrombocytopenia was noted in 2/2 patients. WHO grade IV hepatotoxicity and WHO grade III cardiotoxicity were noted in a patient with preexisting heart disease. Five patients were treated with 12.5 mg/m2 DOXeq. Maximal toxicity at this dose level was WHO grade III thrombocytopenia and local phlebitis (WHO grade II) in 1/5 patients, elevation of alkaline phosphatase (WHO grade III) and WHO grade III vomiting in another patient. Subsequently, five patients received 20 mg/m2 DOXeq. Hepatotoxicity was noted in 5/5 patients (1 × WHO grade IV, 1 × WHO grade III). Thrombocytopenia was noted in 3/5 patients (1 × WHO grade IV, 2 × WHO grade III). At 12.5 mg/m2 DOXeq, a patient diagnosed with a malignant fibrous histiocytoma had stable disease for 4 months. Pharmacokinetic analyses of total and free doxorubicin were performed in plasma and urine. The maximum peak plasma concentration (ppc) for total DOX was 12.3 μg/ml at 40 mg/m2 DOXeq. The area under the plasma concentration time curve (AUC) ranged from 28.83–80.21 μg/ml*h with dose-dependent elimination half lives (t1/2α: 0.02–0.87 h;1/2β: 2.69–11.58 h;1/2γ: 41.44–136.58 h). We conclude that the maximal tolerated dose (MTD) of AD-70 using this schedule is 40 mg/m2 DOXeq. The recommended dose for clinical phase II studies is 12.5 mg/m2 DOXeq.

Key words

phase I dextran-conjugated doxorubicin pharmacokinetics 

Abbreviations

ALT

Alanine Aminotransferase

AST

Aspartate Aminotransferase

DOX

Doxorubicin

DOXeq

Doxorubicin Equivalent

ECG

Electrocardiogram

HPLC

High Pressure Liquid Chromatography

LD10

Lethal Dose for 10% of individuals

MTD

Maximal Tolerated Dose

ppc

Peak Plasma Concentration

WHO

World Health Organisation

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Copyright information

© Kluwer Academic Publishers 1993

Authors and Affiliations

  • Susanne Danhauser-Riedl
    • 1
  • Edith Hausmann
    • 2
  • Hans-D. Schick
    • 1
  • Rita Bender
    • 3
  • Hermann Dietzfelbinger
    • 1
  • Johann Rastetter
    • 1
  • Axel-R. Hanauske
    • 1
  1. 1.Department of Medicine I, Division of Hematology/OncologyTechnische Universität MünchenMunich 80
  2. 2.Medizinische HochschuleInstitute of ToxicologyHannover
  3. 3.Alpha Therapeutic GmbHLangenGermany

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