PHARMACOKINETIC AND BIOTRANSFORMATION STUDIES OF ORMAPLATIN IN CONJUNCTION WITH A PHASE-I CLINICAL-TRIAL

Ormaplatin is a second-generation platinum (Pt) analogue with in vitro activity against some cisplatin-resistant malignant cell lines. We ha ve evaluated the pharmacokinetics and biotransformations of ormaplatin during a phase I trial in which ormaplatin was administered by daily 30-min infusions on 5 consecutive days every 28 days. Sixteen patients received 25 courses at doses ranging from 5.0 to 11.6 mg/M2 per day. Pharmacokinetic parameters determined for ultrafilterable Pt measured by atomic absorption spectrophotometry revealed a short half-life (t1/ 2 16 min), moderate volume of distribution (Vd 12 l/m2), and relativel y fast systemic clearance (Cls 544 ml/min per M2). Cls and percentage of drug unbound decreased during the 5-day administration period. Aver age systemic exposure increased with dose; however, inter-individual v ariability in Cls produced overlap in systemic exposure between the do se levels. The major active biotransformation product [PtCl2(dach)] wa s evaluated at the highest dose level by HPLC. This product decayed mo noexponentially with a mean t1/2 of 13 min and a higher degree of phar macokinetic variability than that of ultrafilterable Pt at this dose. No unreacted ormaplatin was detected; however, several inactive biotra nsformation products persisted for at least 120 min. Approximately 32% of the dose was excreted in the urine during the first day, one-third of this during the initial 1.5 h. The human pharmacokinetic character istics of ormaplatin resemble those of cisplatin; however, additional study will be required to discern which analyte of ormaplatin correlat es best with clinical effects.