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A phase I trial of high-dose continuous-infusion hydroxyurea
D C Smith1, W P Vaughan, P R Gwilt
1Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Cancer Chemotherapy and Pharmacology
|January 1, 1993
Summary
Continuous intravenous hydroxyurea infusions were evaluated in 30 patients. The maximum tolerated doses were determined for 24- and 48-hour infusions, with marrow suppression as the dose-limiting toxicity.
Area of Science:
- Pharmacology
- Oncology
- Pharmacokinetics
Background:
- Hydroxyurea inhibits DNA repair by depleting deoxynucleotides.
- Prolonged exposure to hydroxyurea may enhance therapeutic efficacy.
- Intravenous administration allows for controlled drug delivery.
Purpose of the Study:
- To determine the maximum tolerated doses (MTD) of intravenous hydroxyurea.
- To evaluate MTD for 24-hour and 48-hour continuous infusion schedules.
- To assess pharmacokinetic and pharmacodynamic properties of intravenous hydroxyurea.
Main Methods:
- A phase I clinical trial involving 30 patients.
- Hydroxyurea administered as a 24-hour or 48-hour continuous infusion with a bolus.
- Dose escalation to determine MTD, with toxicity monitoring.
Main Results:
- MTD for 24-h infusion: 13,520 mg/m2 (bolus 1,690 mg/m2), steady-state 1.93 mM.
- MTD for 48-h infusion: 17,576 mg/m2 (bolus 2,197 mg/m2), steady-state 1.43 mM.
- Dose-limiting toxicity was marrow suppression (neutropenia, thrombocytopenia); saturable drug elimination observed.
Conclusions:
- Intravenous hydroxyurea can be administered at higher doses via 48-hour infusion compared to 24-hour infusion.
- Marrow suppression is the primary toxicity, correlating with plasma levels.
- Saturable pharmacokinetics suggest dose adjustments may be necessary.