Relation between dose, plasma concentration and toxicity in a phase I trial using high dose intermittent...

Diacetyldianhydrogalactitol (DADAG), a new alkylating sugar alcohol derivative, was administered as single, 30-min infusions in doses ranging from 390 to 1200 mg/m2. The dose-limiting toxicity was myelosuppression. The median times to WBC nadir and regeneration were 16 and 21 days, and to platelet nadir and recovery 20 and 27, respectively. Nausea and vomiting occurred frequently and were of moderate severity. For phase II studies 900 mg/m2 DADAG given every 4-6 weeks is recommended. The area under the plasma concentration time curve (AUC) for DADAG did not increase in proportion with dose escalation; it changed only from 235.5 +/- 70.7 to 262.4 +/- 71.5 micrograms h ml-1 between doses of 690 and 1050 mg/m2. No correlations between the dose administered and the nadir values for haemoglobin concentration, WBC and platelet counts, or the number of episodes of vomiting were demonstrable in this dose range. Such an association was revealed, however, when the above biological variables were related to the individual AUC for DADAG.