1. Phase I and pharmacokinetic studies of DON.
- Author
-
Kovach JS, Eagan RT, Powis G, Rubin J, Creagan ET, and Moertel CG
- Subjects
- Diazooxonorleucine adverse effects, Diazooxonorleucine metabolism, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Evaluation, Female, Half-Life, Humans, Infusions, Parenteral, Injections, Intravenous, Male, Vomiting chemically induced, Azo Compounds administration & dosage, Diazooxonorleucine administration & dosage, Neoplasms drug therapy
- Abstract
DON, a glutamine antagonist, was administered iv to 26 patients with advanced cancer either once every 3 wks or daily for 3 days every 3 wks to determine toxicity and to look for evidence of therapeutic effect. Total doses ranged from 150 to 600 mg/m2. The single-day schedule produced intolerable nausea and vomiting and no evidence of cytotoxicity at 450-550 mg/m2 given over 10 mins or over 4 hrs. On the 3-day schedule, patients had tolerable gastrointestinal toxic effects at total doses up to 480 mg/m2 given in three equally divided doses by 10-min infusion. This dose also produced cytotoxic activity manifested as transient mild leukopenia and, rarely, thrombocytopenia. No objective responses were seen. Analysis of the plasma elimination of DON demonstrated dose-dependent pharmacokinetic behavior. The parent compound was not detectable in the urine of any patient, indicating extensive metabolism of the drug.
- Published
- 1981