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. It has been used in a variety of malignancies and is usually given orally. Deoxynucleotide depletion is directly related to the concentration of and duration of exposure to hydroxyurea; thus, prolonged continuous infusion may result in increased therapeutic efficacy. A total of 30 patients were treated on this trial, designed to determine the maximum tolerated, doses (MTD) of intravenous hydroxyurea given as a 24-or 48-h continuous infusion. The MTD for the 24-h infusion was 13,520 mg/m² following a bolus of 1,690 mg/m², and the mean (±SD) plasma steady-state concentration was 1.93±0.52 mM. For the 48-h infusion, the MTD was 17,576 mg/m² following a bolus of 2,197 mg/m² and the mean steady-state level was 1.43±0.31 mM. The doselimiting toxicity on both schedules was marrow suppression manifesting as, neutropenia and thrombocytopenia. Pharmacokinetic analysis revealed decreasing clearance with increasing dose, implying that drug elimination is saturable. Pharmacodynamic analysis showed a slight correlation between steady-state plasma levels and the degree of marrow suppression.This work was supported in part by grants 5T32-CA-09307, P30-A-14236-18, and 5-R01-CA45529 from the National Institutes of Health and the National Cancer Institute and by the P.B. Cohen Memorial Fund