Possible correlation between ormaplatin biotransformations and neurotoxicity

Clinical development of ormaplatin has been delayed because of neurotoxicity that was not predictable on the basis of patient characteristics, total cumulative dose, or plasma pharmacokinetics. We report a detailed comparison of the plasma biotransformations of ormaplatin in two patients at the 123 mg/m2-dose administered as a 1-h infusion every 4 weeks. One of these patients developed neurotoxicity after 2 cycles (total cumulative dose = 246 mg/kg), while the other patient showed no symptoms of neurotoxicity through 2 cycles. The maximum plasma concentration and area under the curve for ultrafilterable platinum were greater for the patient that did not develop neurotoxicity. However, both maximum plasma concentration and area under the curve were greater for dichloro(d,l-trans)1,2-diaminocyclohexanedichloroplatinum(II), the major active biotransformation product of ormaplatin, in the patient that developed neurotoxicity. In addition, analysis of plasma biotransformation products suggested that the initial plasma concentrations of ormaplatin were also greater in the patient that developed neurotoxicity. These data suggest that analysis of individual plasma biotransformation products may be useful in predicting toxicity of platinum anticancer agents and should be included in future phase I studies.