Clinical toxic effects of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (IMPY) with relevant pharmacokinetic parameters

2,3-Dihydro-1H-imidazo[1,2-b]pyrazole (IMPY) is an inhibitor of ribonucleotide reductase and of DNA synthesis selected for clinical trials because of its activity against L1210 leukemia variants resistant to other inhibitors of this enzyme. A phase I trial designated to allow in-depth pharmacologic evaluation has recently been completed and the clinical results and preliminary pharmacokinetic data are reported here. Each patient received IMPY by three different schedules. A single iv bolus, intermittent 5-day bolus, and 5-day continuous infusion were given at 3-week intervals. The major dose-limiting toxic effects were vomiting, rbc hemolysis, confusion, and somnolence. All toxic effects seemed to be dose- and schedule-dependent and were readily reversible. IMPY enters the cerebrospinal fluid and is highly concentrated in gastric secretions. Clearance of IMPY is impaired in the presence of hepatic insufficiency. Eighteen of 26 patients entered are evaluable for response, including one patient with colon cancer with minimal response and three patients with stable disease.