Annals of Oncology 2:589-596, 1991
© 1991 European Society for Medical Oncology
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Original article: Phase I clinical and pharmacokinetic study of zeniplatin, a new platinum complex
1Institut Jules Bordet Brussels, Belgium
2University of Maryland Cancer Center Baltimore, Maryland, USA
3Cyanamid Benelux, Mont Saint Guibert Belgium
4American Cyanamid Company, Medical Research Division Pearl River, N. Y, USA
Correspondence to: Dr M. J. Piccart, Institut Jules Bordet, Rue Heger Bordet 1, B-1000 Brussels, Belgium
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.
phase I trial, zeniplatin, platinum analogs
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