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

Br J Cancer. 1988 Jul;58(1):70-2. doi: 10.1038/bjc.1988.164.

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.

MeSH terms

  • Adult
  • Aged
  • Drug Evaluation
  • Female
  • Humans
  • Hydroxamic Acids / adverse effects
  • Hydroxamic Acids / pharmacokinetics
  • Hydroxamic Acids / therapeutic use*
  • Liver Function Tests
  • Male
  • Middle Aged
  • Nausea / chemically induced
  • Neoplasm Metastasis
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Ribonucleotide Reductases / antagonists & inhibitors*
  • Urination Disorders / chemically induced
  • Vomiting / chemically induced

Substances

  • Hydroxamic Acids
  • Ribonucleotide Reductases
  • 3,4-dihydroxybenzohydroxamic acid