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

Abstract

A Phase I study of intravenous (IV) bolus 4'-O-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/mz, 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 ' /z a (+SE) of 2.5 f 0.85 minutes, TB l/z of 25.6 rt 6.5 minutes, and T y of 23.6-t 7.6 hours. The area under the curve was 537-t 149 ng/ml X hours, volume of distribution (V,) 3504 t 644 l/mz, and total clearance ((21,) was 204 + 39.3 l/hour/mz. Adriamycinol, doxorubicin, adriamycinone, and tetrahydropyranyladriamycinol were the metabolites detected in plasma and the amount of doxorubicin was I 10% of the total metabolites. Urinary excretion of Pirarubicin in the first 24 hours was I 10%. Activity was noted in mesothelioma, leiomyosarcoma, and basal cell carcinoma. The recommended starting dose for Phase I1 trials is 60 mg/m2 IV bolus every 3 weeks. Cancer 66:2082-2091,1990. IRARUBICIN (4'-0-tetrahydropyranyladriamycin) is a P synthetic analog of doxorubicin (Adriamycin). ' Pi-rarubicin (THP-Adriamycin) exhibited similar or greater antitumor activity than doxorubicin in experimental tu

Extract from Dioscorea bulbifera L. rhizomes aggravate pirarubicin-induced cardiotoxicity by inhibiting the expression of P-glycoprotein and multidrug resistance-associated protein 2 in the mouse liver

“…Cardiotoxicity is the main adverse effect of THP. K S Sridhar et al had reported that there was no cardiotoxicity with a cumulative dose of 300 mg/m 2 THP 15 . The drug administration plan was based on the methods in literature and preliminary work of our group 16 , 17 .…”

Prevention of Peritoneal Carcinomatosis from Colon Cancer Cell Seeding Using a Pirarubicin Solution in Rats and Nude Mice

“…In contrast with povidone‐iodine, IP pirarubicin at 50 mg/l for 15 minutes has no toxic effect on rat peritoneum, so local tolerance might be good in humans. The maximally recommended dose of pirarubicin given by the intravenous route is 60 mg/m 2 [39]. As most of the drug would be flushed after a 15 minute washing, a total dose of 100 mg pirarubicin diluted in 2 liters of a NaCl solution (final concentration 50 mg/l) could be used for peritoneal washing without the risk of adverse systemic effects.…”