title: Phase I clinical trial and pharmacokinetic evaluation of 4'-0-tetrahydropyranyladriamycin (THP-adriamycin).
abstract: Tetrahydropyranyladriamycin (THP-adriamycin) is an anthracycline analogue currently under development in Europe and Japan. Preclinical studies suggest that it may have greater activity and less cardiac toxicity than doxorubicin. We conducted a phase I clinical and pharmacologic study of THP-adriamycin given as a weekly 15-min infusion for 3 weeks, followed by 1 week of observation. Therapy was associated with minimal acute toxicity. The dose-limiting toxicity was neutropenia, usually maximal during the 4th week after treatment; alopecia was rare. The maximum tolerated dose was 25 mg/m2; for phase II studies using this schedule, a dose of 20 mg/m2 weekly for 3 weeks is recommended. Pharmacokinetic studies revealed a triphasic elimination of the parent compound with alpha, beta, and gamma half-lives of 5.6 min, 1.4 h, and 9.3 h, respectively. THP-adriamycin was rapidly taken up by blood cell components, with concentrations in red blood cells (RBCs), lymphocytes, and polymorphonuclear cells exceeding those in plasma. In all, less than 10% of the compound was eliminated in the urine within 24 h.
authors.affiliation: Department of Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
authors.forename: M N
authors.initials: MN
authors.lastname: Raber
authors.forename: R A
authors.initials: RA
authors.lastname: Newman
authors.forename: K
authors.initials: K
authors.lastname: Lu
authors.forename: S
authors.initials: S
authors.lastname: Legha
authors.forename: C
authors.initials: C
authors.lastname: Gorski
authors.forename: R S
authors.initials: RS
authors.lastname: Benjamin
authors.forename: I H
authors.initials: IH
authors.lastname: Krakoff
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D004341:Drug Evaluation; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors
chemical_list: D004317:Doxorubicin; C027260:pirarubicin