Clinical pharmacology and pharmacokinetics of cis-platinum and analogs

cis-Platinum (DDP), the first metal coordination complex introduced into clinical trials, is remarkable for its therapeutic index. A short review of the numerator of this index, ie, the clinical activities of DDP given as a single agent or in combination therapy is presented. Toxicity of DDP, the denominator of the index, is given more attention, particularly nephrotoxicity, whose cumulative character and molecular mechanism are still in question and which can most often be prevented by following certain safety rules that are detailed in this paper. Pharmacokinetics data of free and filterable platinum are reviewed and discussed according to the different modalities of administration of DDP, and to what is known about its toxicity and its mechanism of cell kill. The rationale for using DDP in combination treatment is presented and the question of possible long-term toxicities is raised. cis-platinum analogs are sought for the purpose of enlarging the spectrum of activity, increasing selectivity and diminishing toxicity. Malonato-platinum has been shown not to be cross-resistant with DDP and to be clinically effective in adult acute leukemia. In a phase I study, malonato-platinum, which is poorly soluble, was administered in 6-24-hour infusions to 49 patients in doses ranging from 3 to 32 mg/kg. GI toxicity was universal. Hematological toxicity appeared to be mild and not clearly dose-related (the 3-32 mg/kg patients were not yet evaluable). Platinum pharmacokinetics in urine and plasma were performed using flameless absorption spectrophotometry. Preliminary results have suggested that malonato-platinum presented several pharmacokinetic features in common with DDP. Minor responses were seen in four solid tumor patients, three of whom were refractory to DDP. Other analogs soon to be introduced into clinical trials are listed.