A phase 1 and pharmacokinetic study of didox: A ribonucleotide reductase inhibitor

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Abstract
A phase 1 study of a new ribonucleotide reductase inhibitor, didox, was performed by administration of escalating doses of the drug by slow i.v. injection. Thirty-four patients with unresponsive metastatic carcinoma received the drug. There were 13 escalations of dosage, from a starting dose of 192 mg m-2 to 10 g m-2. Dose limiting toxicity was encountered at 7.5 g m-2 where disturbances of hepatic and renal function were observed, in addition to severe gastrointestinal toxicity. Pharmacokinetic studies showed that a peak level of didox was achieved within 5 minutes of injection. At 1,728 mg m-2 the data best fitted a 2 compartment open model, with a mean serum alpha t1/2 of 5.2 min, with a beta t1/2 of 41.3 min. Less than 10% of the drug was excreted unchanged in the urine and the majority of this excretion was within 6 h. Didox can therefore be safely given by slow i.v. injection at a dose of 6 g m-2.