PHARMACOKINETICS AND TOXICITY OF 120-HOUR CONTINUOUS-INFUSION HYDROXYUREA IN PATIENTS WITH ADVANCED SOLID TUMORS

A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The d ose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/m(2) per day. The primary dose-limiting toxicity was neutropeni a, often accompanied by leukopenia, thrombocytopenia and generalized s kin rash. Prophylactic treatment of patients with dexamethasone and di phenhydramine hydrochloride prevented the skin rash, but not the hemat opoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were L inearly correlated with the dose (R(2) = 0.71, n = 18, P < 0.0001). Th e mean +/- SE concentrations were 93 +/- 16, 230 +/- 6 and 302 +/- 27 mu M at 1, 2 and 3.2 g/m(2) per day, respectively. The mean +/- SE ren al and nonrenal clearances of hydroxyurea were 2.14 +/- 0.18 and 3.39 +/- 0.28 l/h per m(2) (n = 16), neither of which correlated with the d ose. The concentration of hydroxyurea in plasma decayed monoexponentia lly with a mean +/- SE half-life of 3.25 +/- 0.18 h (n = 17). The stea dy-state concentration of hydroxyurea was >200 mu M in all nine patien ts treated at 2 g/m(2) per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with o ther antineoplastic agents.