Phase I clinical and pharmacokinetic study of an one-hour infusion of ormaplatin (NSC 363812)

1573-0646

chemotherapy ; platinum (IV) analogues ; cisplatin resistance ; pharmacodynamics

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

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 ≤ 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 (t1/2β) 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.

Electronic Resource