Studies of hydroxyurea administered by continuous infusion. Toxicity, pharmacokinetics, and cell synchronization

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Abstract
Hydroxyurea was administered by means of two schedules designed to provide continuous 72‐hour exposure of tumor cells to therapeutic drug levels. Toxicity and pharmacokinetics were determined for both an oral pulse dose schedule (every 4 hours × 18 doses) and continuous intravenous (IV) infusion for 72 hours. The maximal tolerated dose (MTD) was 800 mg/m2 every 4 hours for the oral route and 3.0 mg/m2/min × 72 hours for IV infusion. Granulocytopenia was dose‐limiting for both schedules and correlated well with plasma‐HU levels. Serial sampling of normal bone marrow (10 patients) and tumor tissue (3 patients) showed a modest degree of synchronization induced by continuous IV infusion of hydroxyurea. Interindividual pharmacokinetic variations severely limit the usefulness of the oral pulse schedule as a potential means of synchronizing cells. Hydroxyurea administered by continuous IV infusion may be useful as a synchronizing agent in humans. Cancer 46:455–462, 1980.