A PHASE-I TRIAL OF HIGH-DOSE CONTINUOUS-INFUSION HYDROXYUREA

Hydroxyurea inhibits ribonucleotide reductase, resulting in depletion of intracellular deoxynucleotide pools and inhibition of DNA repair. I t has been used in a variety of malignancies and is usually given oral ly. Deoxynucleotide depletion is directly related to the concentration of and duration of exposure to hydroxyurea; thus, prolonged continuou s infusion may result in increased therapeutic efficacy. A total of 30 patients were treated on this trial, designed to determine the maximu m tolerated doses (MTD) of intravenous hydroxyurea given as a 24- or 4 8-h continuous infusion. The MTD for the 24-h infusion was 13,520 mg/m (2) following a bolus of 1,690 mg/m(2), and the mean (+/- SD) plasma s teady-state concentration was 1.93 +/- 0.52 mM. For the 48-h infusion, the MTD was 17,576 mg/m(2) following a bolus of 2,197 mg/m(2) and the mean steady-state level was 1.43 +/-0.31 mM. The dose-limiting toxici ty on both schedules was marrow suppression manifesting as neutropenia and thrombocytopenia. Pharmacokinetic analysis revealed decreasing cl earance with increasing dose, implying that drug elimination is satura ble. Pharmacodynamic analysis showed a slight correlation between stea dy-state plasma levels and the degree of marrow suppression.