PHARMACOKINETICS OF ELEMENTAL PLATINUM (ULTRAFILTRATE AND TOTAL) AFTER A 30 MINUTE INTRAVENOUS-INFUSION OF ORMAPLATIN

Preclinical data suggest that ormaplatin chloro-(d1-trans)-1,2-diammin ocyclohexaneplatinum) has substantial activity in cisplatin-resistant tumor models and may be less nephrotoxic than cisplatin. Based on thes e data we initiated a phase I clinical trial in patients with refracto ry metastatic cancer. This report characterizes the pharmacokinetic pr ofile of both the total plasma concentrations of elemental platinum an d the unbound ultrafiltrate concentrations of elemental platinum, foll owing a 30 min intravenous infusion of ormaplatin. Platinum concentrat ions were determined by AAS, and pharmacokinetic parameters for both t he total plasma concentration and the ultrafiltrate concentration of e lemental platinum were determined using both compartmental and noncomp artmental methods. Twenty-eight patients (14 males and 14 females; med ian age, 58) received ormaplatin. There was a linear relationship betw een C-max and dose (r(2)=0.945) and AUC and dose (r(2)=0.976). Ormapla tin is more accurately described by a two-compartment model than by a one-compartment model. The distribution half-life (t(1/2 alpha)) was 0 .3 h and the terminal half-life (t(1/2 beta)) was 39.1 h. The volume o f the central compartment (V) was 68.6 L and the volume of distributio n at steady state (V-dss) was 183 L. Like total plasma platinum, unbou nd platinum is also best characterized by a two-compartment model. The elimination of free platinum is also biphasic with a distribution hal f-life (t(1/2 alpha)) of 0.3 h and a terminal half-life (t(1/2 beta)) of 19.3 h. The mean volume of the central compartment (V) was 200.5 L, and the mean volume of distribution at steady state (V-dss) was 560.5 L. Clinical development of ormaplatin has been terminated due to incr eased frequency of neurological complications noted over other platinu m agents; however, the pharmacokinetics are, in general, similar to th ose of other clinically used platinum compounds. (C) 1997 by John Wile y & Sons, Ltd.