A PHASE-I AND PHARMACOKINETIC STUDY OF DIDOX ADMINISTERED BY 36-HOUR INFUSION

Twelve patients were treated with didox, a new ribonucleotide reductase inhibitor, by 36 h infusion. The maximum tolerated dose was 6gm-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 6gm-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 fig ml-1 h_l compared to 232 pg 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 fig ml-1 h-1. In contrast, the amide metabolite was not detected following the 36 h infusion, but AUC values of 23 fig ml-1 h-l were seen after the 30 min infusion. The mean peak plasma level was 72 fig ml-1 following 6gm-2 given by a 30 min infusion compared to 2.8 fig ml-1following the prolonged infusion. Clearance was higher following the 36 h infusion: 97.6 versus 24.4 l h-1. © Macmillan Press Ltd., 1990.