A CLINICAL PHARMACOKINETICS STUDY OF CARZELESIN GIVEN BY SHORT-TERM INTRAVENOUS-INFUSION IN A PHASE-I STUDY

We investigated the pharmacokinetic behavior of carzelesin in 31 patie nts receiving this drug by 10-min intravenous infusion in a Phase I cl inical trial, which was conducted at institutions in Nijmegen (institu tion 1) and Brussels (institution 2). The dose steps were 24, 48, 96, 130, 150, 170, 210, 250, and 300 mu g/m(2). Carzelesin is a cyclopropy lpyrroloindole prodrug that requires meta belie activation via U-76,07 3 to U-76,074. The lower limit of quantitation (LLQ) of the high-perfo rmance liquid chromatography (HPLC) method used in this study was 1 ng /ml for the parent drug and its metabolic products. Carzelesin was rap idly eliminated from plasma (elimination half-life 23 +/- 9 min; mean value +/- SD). At all dose levels, U-76,073 was found as early as in t he first samples taken after the start of the infusion. However, the c oncentration of U-76,074 exceeded the LLQ for only short periods and o nly at the higher dose levels. Although the plasma levels of all three compounds were well above the respective IC50 values obtained by in v itro clonogenic assays, they were much lower than those observed in a preclinical study in mice. There was a substantial discrepancy in the mean plasma clearance observed between patients from institution 1 (7. 9 +/- 2.1 l h(-1) m(-2)) and those from institution 2 (18.4 +/- 13.6 l h(-1) m(-2); P = 0.038), probably reflecting problems with drug admin istration in the latter institution. The results recorded for patients in institution 1 indicated that the AUC increased proportionately wit h increasing doses. There was a good correlation between the maximal p lasma concentration and the AUG, enabling future monitoring of drug ex posure from one timed blood sample. Urinary excretion of carzelesin wa s below 1% of the delivered dose.