Wp. Petros et al., PHARMACOKINETIC AND BIOTRANSFORMATION STUDIES OF ORMAPLATIN IN CONJUNCTION WITH A PHASE-I CLINICAL-TRIAL, Cancer chemotherapy and pharmacology, 33(4), 1994, pp. 347-354
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.