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Phase I clinical trial and pharmacokinetic evaluation of 4′-0-tetrahydropyranyladriamycin (THP-adriamycin)

Summary

Tetrahydropyranyladriamycin (THP-adriamycin) is an anthracycline analogue currently under development in Europe and Japan. Preclinical studies suggest that it may have greater activity and less cardiac toxicity than doxorubicin. We conducted a phase I clinical and pharmacologic study of THP-adriamycin given as a weekly 15-min infusion for 3 weeks, followed by 1 week of observation. Therapy was associated with minimal acute toxicity. The dose-limiting toxicity was neutropenia, usually maximal during the 4th week after treatment; alopecia was rare. The maximum tolerated dose was 25 mg/m2; for phase II studies using this schedule, a dose of 20 mg/m2 weekly for 3 weeks is recommended. Pharmacokinetic studies revealed a triphasic elimination of the parent compound with α, β, and γ half-lives of 5.6 min, 1.4 h, and 9.3 h, respectively. THP-adriamycin was rapidly taken up by blood cell components, with concentrations in red blood cells (RBCs), lymphocytes, and polymorphonuclear cells exceeding those in plasma. In all, <10% of the compound was eliminated in the urine within 24 h.

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Abbreviations

THP:

adriamycin

4′0:

tetrahydropyranyladriamycin

HPLC:

high-pressure liquid chromatography

AUC:

area under the curve

Vd:

volume of distribution

PMN:

polymorphonuclear neutrophil lymphocytes

RBC:

red blood cell

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Author information

Correspondence to M. N. Raber.

Additional information

Supported in part by a National Cancer Institute Research Career Development Award (KO4 CA 01135) to R. A. Newman

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Raber, M.N., Newman, R.A., Lu, K. et al. Phase I clinical trial and pharmacokinetic evaluation of 4′-0-tetrahydropyranyladriamycin (THP-adriamycin). Cancer Chemother. Pharmacol. 23, 311–315 (1989). https://doi.org/10.1007/BF00292410

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Keywords

  • Doxorubicin
  • Neutropenia
  • Acute Toxicity
  • Anthracycline
  • Parent Compound