PHARMACOKINETICS OF 15-DEOXYSPERGUALIN STUDIED IN RENAL-TRANSPLANT PATIENTS RECEIVING THE DRUG DURING GRAFT-REJECTION

The pharmacokinetics of the novel immunosuppressant 15-deoxyspergualin (DSG) were studied in five renal transplant patients who participated in a dose-finding study for the treatment of renal graft rejection. D SG, in a dose of 4 or 6 mg/kg per day, was given in a 3-h i. v. infusi on for 5 days, in combination with a 4-day course of i. v. methylpredn isolone. Analyses of DSG in plasma and urine were performed by highper formance liquid chromatography (HPLC). Plasma samples were taken up to 12 h following infusion on treatment day 2 and again on day 4 or 5. U rine was collected during the infusion and up to 12 h following the in fusion. DSG was rapidly eliminated from the plasma in an apparently bi exponential manner. The mean t1/2alpha was 0.5 h (range 0.1-1.1 h) and the mean t1/2 beta 2.4 h (range 1.0-5.9 h). The mean Cmax was 4117 ng /ml (range 1944-7166 ng/ml) and the mean AUC 12 505 ng.ml(-1).h (range 5642-24 435 ng.ml(-1).h). Clearance ranged from 375 to 945 ml/min (me an 653 ml/min) and volume of distribution ranged from 0,2 to 1,4 l/kg (mean 0,7 l/kg). A small fraction (mean 1.6 %, range 0.1%-2.7%) of the DSG dose given was excreted unmetabolized in the urine. The amount of DSG in the urine correlated strongly to renal function (P = 0.0019). Pharmacokinetics were otherwise not affected by the degree of renal fu nction. There were no significant differences in the pharmacokinetic d eterminants and no accumulation of the drug on study day 4 or 5, as co mpared to day 2. Therefore, the drug can safely be given to patients w ith impaired renal function. DSG did not affect cyclosporin pharmacoki netics.