A phase I and pharmacokinetic study of didox administered by 36 hour infusion. The Cancer Research Campaign Phase I/II Clinical Trials Committee.
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.
Carmichael
J
J
ICRF Department of Clinical Oncology, Churchill Hospital, Headington, Oxford, UK.
Cantwell
B M
BM
Mannix
K A
KA
Veale
D
D
Elford
H L
HL
Blackie
R
R
Kerr
D J
DJ
Kaye
S B
SB
Harris
A L
AL
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*
D006877:Hydroxamic Acids; D012264:Ribonucleotide Reductases; C035419:3,4-dihydroxybenzohydroxamic acid