Sakata M, Chaney S G, Spriggs D R
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill 27599-7260, USA.
Oncol Res. 1995;7(2):67-71.
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.
奥马铂的临床开发因神经毒性而延迟，这种神经毒性无法根据患者特征、总累积剂量或血浆药代动力学来预测。我们报告了两名患者在每4周静脉输注1小时、剂量为123mg/m²的情况下奥马铂血浆生物转化的详细比较。其中一名患者在2个周期后（总累积剂量=246mg/kg）出现神经毒性，而另一名患者在2个周期内未出现神经毒性症状。未发生神经毒性的患者超滤铂的最大血浆浓度和曲线下面积更高。然而，在出现神经毒性的患者中，奥马铂的主要活性生物转化产物二氯（d，l-反式）1,2-二氨基环己烷二氯铂（II）的最大血浆浓度和曲线下面积均更高。此外，血浆生物转化产物分析表明，出现神经毒性的患者中奥马铂的初始血浆浓度也更高。这些数据表明，对个体血浆生物转化产物的分析可能有助于预测铂类抗癌药物的毒性，应纳入未来的I期研究。
