Clinical and Pharmacokinetic Studies on the New Platinum Complex Zeniplatin (CL286,558)
In an effort to develop more active and less toxic analogues of cisplatin, zeniplatin (code number: CL 286,558; [2, 2-Bis (aminomethyl)-1, 3-propanediol-N,N′] [1, 1-cyclobutane dicarboxylato]-(2-) -0,0′] Platinum (Pt)) has been synthesized (American Cyanamid Company, Pearl River, NY). This new agent has a molecular weight of 471.38 and is much more water soluble than cisplatin. The compound was selected for a phase I clinical and pharmacokinetic trial on the basis of its high therapeutic index and its broad spectrum of antitumor activity against human xenografts implanted in nude mice and murine solid tumor models. Its activity against B16 melanoma and M5076 reticulum cell sarcoma murine tumor models is higher than for both cisplatin and carboplatin1,2. In animal models, zeniplatin was found to be less myelosuppressive and nephrotoxic than cisplatin at therapeutic dosage. The exact mechanism of action of this compound has not been elucidated yet2. We here report the results of the phase I clinical trial performed at the Institut Jules Bordet and of the preliminary pharmacokinetic studies. Since other Pt analogues are known to extensively bind to plasma proteins, an in vitro study of the rate and extent of protein binding was also accomplished.
KeywordsHigh Therapeutic Index Protein Binding Study Bayesian Prior Flameless Atomic Absorption Spectrophotometry American Cyanamid Company
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