A phase i study of 4′‐0‐tetrahydropyranyladriamycin: Clinical pharmacology and pharmacokinetics

Kasi S. Sridhar, T. S.Anantha Samy, Ram P Agarwal, Robert C. Duncan, Pasquale Benedetto, Awtar K. Ganju-Krishan, Charles L. Vogel, Lynn G. Feun, Niramol M. Savaraj, Stephen P. Richman, C. Gordon Zubrod

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

A Phase I study of intravenous (IV) bolus 4'-0-tetrahydropyranyladriamycin (Pirarubicin) was done in 55 patients in good performance status with refractory tumors. Twenty-six had minimal prior therapy (good risk), 23 had extensive prior therapy (poor risk), and six had renal and/or hepatic dysfunction. A total of 167 courses at doses of 15 to 70 mg/m2 were evaluable. Maximum tolerated dose in good-risk patients was 70 mg/m2, and in poor-risk patients, 60 mg/m2. The dose-limiting toxic effect was transient noncumulative granulocytopenia. Granulocyte nadir was on day 14 (range, 4-22). Less frequent toxic effects included thrombocytopenia, anemia, nausea, mild alopecia, phlebitis, and mucositis. Myelosuppression was more in patients with hepatic dysfunction. Pharmacokinetic analyses in 21 patients revealed Pirarubicin plasma T 1/2 α (± SE) of 2.5 ± 0.85 minutes, Tβ 1/2 of 25.6 ± 6.5 minutes, and T 1/2 γ of 23.6 ± 7.6 hours. The area under the curve was 537 ± 149 ng/ml x hours, volume of distribution (V(d)) 3504 ± 644 l/m2, and total clearance (Cl(T)) was 204 + 39.3 l/hour/m2. Adriamycinol, doxorubicin, adriamycinone, and tetrahydropyranyladriamycinol were the metabolites detected in plasma and the amount of doxorubicin was ≤ 10% of the total metabolites. Urinary excretion of Pirarubicin in the first 24 hours was ≤ 10%. Activity was noted in mesothelioma, leiomyosarcoma, and basal cell carcinoma. The recommended starting dose for Phase II trials is 60 mg/m2 IV bolus every 3 weeks.

Original languageEnglish (US)
Pages (from-to)2082-2091
Number of pages10
JournalCancer
Volume66
Issue number10
DOIs
StatePublished - Nov 15 1990

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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