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

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.