title: Phase I clinical and pharmacokinetic study of an one-hour infusion of ormaplatin (NSC 363812).
abstract: Ormaplatin (NSC 363812, tetraplatin) is a stable platinum (IV) analog which has exhibited activity against cisplatin-resistant cell lines. A phase I trial of ormaplatin administered as a 1-h infusion every 4 weeks was performed. Forty-one patients received 101 cycles of drug over the dose range 4-128 mg/m2. The dose-limiting toxicity was reversible thrombocytopenia and granulocytopenia. Minimal myelosuppression was observed at dose levels < or = 78 mg/m2, while grade 3 or 4 myelosuppression (thrombocytopenia and/or granulocytopenia) was seen in 4/8 patients at 98 mg/m2 and 4/5 patients at 123 mg/m2. Nausea and vomiting was observed at all dose levels but was controlled with antiemetic premedication. Neurotoxicity was observed in 5/41 patients and the incidence appeared related to cumulative dose rather than to dose level or drug clearance. Platinum was measured by furnace atomic absorption spectrophotometry. Ormaplatin-derived plasma ultrafilterable platinum (UF-Pt) exhibited linear pharmacokinetics over the dose range studied. The mean total body clearance of UF-Pt was 135 ml/min/m2 and the mean elimination half-life (t1/2beta) was 13.6 h. Ormaplatin exhibited a high degree of protein binding, with more than 70% of platinum protein bound by the end of the infusion. Urinary excretion of platinum accounted for 37% of the total dose of ormaplatin in 24 hours. A phase II dose of 98 mg/m2 is recommended for testing in a patient population with cisplatin-refractory disease.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, Madison 53792, USA. kdtutsch@facstaff.wisc.edu
authors.forename: K D
authors.initials: KD
authors.lastname: Tutsch
authors.forename: R Z
authors.initials: RZ
authors.lastname: Arzoomanian
authors.forename: D
authors.initials: D
authors.lastname: Alberti
authors.forename: M B
authors.initials: MB
authors.lastname: Tombes
authors.forename: C
authors.initials: C
authors.lastname: Feierabend
authors.forename: H I
authors.initials: HI
authors.lastname: Robins
authors.forename: D R
authors.initials: DR
authors.lastname: Spriggs
authors.forename: G
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001853:Bone Marrow / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009422:Nervous System Diseases / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D013921:Thrombocytopenia / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C049777:ormaplatin