title: A phase I study of 4'-0-tetrahydropyranyladriamycin. Clinical pharmacology and pharmacokinetics.
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 alpha (+/- SE) of 2.5 +/- 0.85 minutes, T beta 1/2 of 25.6 +/- 6.5 minutes, and T 1/2 gamma of 23.6 +/- 7.6 hours. The area under the curve was 537 +/- 149 ng/ml x hours, volume of distribution (Vd) 3504 +/- 644 l/m2, and total clearance (ClT) was 204 + 39.3 l/hour/m2. Adriamycinol, doxorubicin, adriamycinone, and tetrahydropyranyladriamycinol were the metabolites detected in plasma and the amount of doxorubicin was less than or equal to 10% of the total metabolites. Urinary excretion of Pirarubicin in the first 24 hours was less than or equal to 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.
authors.affiliation: Department of Oncology, Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: K S
authors.initials: KS
authors.lastname: Sridhar
authors.forename: T S
authors.initials: TS
authors.lastname: Samy
authors.forename: R P
authors.initials: RP
authors.lastname: Agarwal
authors.forename: R C
authors.initials: RC
authors.lastname: Duncan
authors.forename: P
authors.initials: P
authors.lastname: Benedetto
authors.forename: A G
authors.initials: AG
authors.lastname: Krishan
authors.forename: C L
authors.initials: CL
authors.lastname: Vogel
authors.forename: L G
authors.initials: LG
authors.lastname: Feun
authors.forename: N M
authors.initials: NM
authors.lastname: Savaraj
authors.forename: S P
authors.initials: SP
authors.lastname: Richman
mesh_terms: D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D012074:Remission Induction; D013318:Stroke Volume / Q000187:drug effects
chemical_list: D004317:Doxorubicin; C027260:pirarubicin