Original article: Phase I clinical and pharmacokinetic study of zeniplatin, a new platinum complex

Abstract

Summary: Forty-six patients with refractory solid malignancies received the new platinum complex [2, 2-bis(aminomethyl)-l, 3-propanediol-N-N'] [l, l-cyclobutanedicarboxylato][(2-)0, 0')] platinum (zeniplatin). Zeniplatin was given, without hydration or mannitol, as a 60- to 90-min i.v. infusion every 3 weeks at doses ranging from 8 to 145 mg/m2. The maximum tolerated dose of zeniplatin was 145 mg/m2. The dose-limiting toxicity of zeniplatin was dose-related leukopenia and neutropenia, with the nadir usually observed between 1 and 2 weeks after therapy and recovery usually occurring by 3 weeks after therapy. Thrombocytopenia was rare. The most prominent non-hematological side-effect of zeniplatin was nausea and vomiting. Other non-hematological side-effects were mild or absent. Zeniplatin did not induce significant neurological or auditory toxicity. Zeniplatin was not nephrotoxic at doses < 120 mg/m2. At 145 mg/m2, the creatinine clearance decreased by a mean of 40% after 2 cycles of therapy. Two patients, one with malignant melanoma and one with renal cell cancer, achieved a partial response. Pharmacokinetics of free (plasma ultrafiltrates) and total platinum in plasma were determined in 5 patients. An in vitro study of the rate and extent of zeniplatin binding to protein in human plasma was also performed. Free and total platinum were measured by flameless atomic absorption spectrometry; free zeniplatin was measured in ultrafiltrate by HPLC. Total and free plasma platinum concentrations were co-modelled using the information from the in vitro study. After a dose of 120 mg/m2 of zeniplatin, the mean (± SD) of the area under the plasma concentration of free platinum versus time curve (AUC) was 11.8 ± 2.3 mg/L hr; the mean terminal 'half-life', based on the concentrations of free platinum at 12 and 24 hrs after the end of infusion, was 9.8 ± 6.2 hr, and the mean total body clearance, 4.3 ± 0.9 L/hr/m2. In vitro and in vivo data suggest that the protein binding of zeniplatin was saturable and dissociation was very slow, if not irreversible. © 1991 Kluwer Academic Publishers.