title: A phase I and pharmacokinetic study of didox administered by 36 hour infusion. The Cancer Research Campaign Phase I/II Clinical Trials Committee.
abstract: Twelve patients were treated with didox, a new ribonucleotide reductase inhibitor, by 36 h infusion. The maximum tolerated dose was 6 g m-2, above which dose-limiting hepatic toxicity was observed. Patient tolerance was significantly better using the 36 h infusion compared to patients receiving the drug by a 30 min infusion; in particular, there were no reports of nausea or vomiting. No responses were seen in these patients. Detailed pharmacokinetics were performed at 6 g m-2 comparing the 36 h and 30 min infusions in four patients. Parent drug AUC values were lower for the 36 h infusion, 67.8 micrograms ml-1 h-1 compared to 232 micrograms ml-1 h-1 for the 30 min infusion. AUC values for the 3-hydroxy metabolite were much higher following the 36 h infusion: 55.4 compared to 18.6 micrograms ml-1 h-1. In contrast, the amide metabolite was not detected following the 36 h infusion, but AUC values of 23 micrograms ml-1 h-1 were seen after the 30 min infusion. The mean peak plasma level was 72 micrograms ml-1 following 6 g m-2 given by a 30 min infusion compared to 2.8 micrograms ml-1 following the prolonged infusion. Clearance was higher following the 36 h infusion: 97.6 versus 24.4 l h-1.
authors.affiliation: ICRF Department of Clinical Oncology, Churchill Hospital, Headington, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Carmichael
authors.forename: B M
authors.initials: BM
authors.lastname: Cantwell
authors.forename: K A
authors.initials: KA
authors.lastname: Mannix
authors.forename: D
authors.initials: D
authors.lastname: Veale
authors.forename: H L
authors.initials: HL
authors.lastname: Elford
authors.forename: R
authors.initials: R
authors.lastname: Blackie
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerr
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
chemical_list: D006877:Hydroxamic Acids; D012264:Ribonucleotide Reductases; C035419:3,4-dihydroxybenzohydroxamic acid