A phase I study of 4'-0-tetrahydropyranyladriamycin. Clinical pharmacology and pharmacokinetics

K. S. Sridhar, T. S. Anantha Samy, R. P. Agarwal, R. C. Duncan, Pasquale W Benedetto, A. G. Krishan, Charles Vogel, Lynn G Feun, Niramol Savaraj, Stephen P Richman, C. G. Zubrod

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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
Pages (from-to)2082-2091
Number of pages10
JournalCancer
Volume66
Issue number10
DOIs
StatePublished - Dec 11 1990

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Clinical Pharmacology
Pharmacokinetics
Poisons
Doxorubicin
Phlebitis
Mucositis
Agranulocytosis
Maximum Tolerated Dose
Leiomyosarcoma
Liver
Basal Cell Carcinoma
Mesothelioma
Alopecia
Granulocytes
Thrombocytopenia
Nausea
Area Under Curve
Anemia
Kidney
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A phase I study of 4'-0-tetrahydropyranyladriamycin. Clinical pharmacology and pharmacokinetics. / Sridhar, K. S.; Anantha Samy, T. S.; Agarwal, R. P.; Duncan, R. C.; Benedetto, Pasquale W; Krishan, A. G.; Vogel, Charles; Feun, Lynn G; Savaraj, Niramol; Richman, Stephen P; Zubrod, C. G.

In: Cancer, Vol. 66, No. 10, 11.12.1990, p. 2082-2091.

Research output: Contribution to journalArticle

Sridhar, K. S. ; Anantha Samy, T. S. ; Agarwal, R. P. ; Duncan, R. C. ; Benedetto, Pasquale W ; Krishan, A. G. ; Vogel, Charles ; Feun, Lynn G ; Savaraj, Niramol ; Richman, Stephen P ; Zubrod, C. G. / A phase I study of 4'-0-tetrahydropyranyladriamycin. Clinical pharmacology and pharmacokinetics. In: Cancer. 1990 ; Vol. 66, No. 10. pp. 2082-2091.
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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.",
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