Phase I and other dose-ranging studies of ondansetron.

Phase I studies of intravenous (IV) ondansetron in cancer patients receiving emetogenic chemotherapy were designed to assess the degree of antiemetic protection and pattern of adverse events produced by ondansetron at various doses. In a study of 44 patients receiving various forms of chemotherapy (including cisplatin), ondansetron was administered in three IV doses 2 hours apart beginning 30 minutes prior to chemotherapy. Antiemetic efficacy was seen at all dose levels (0.04 mg/kg to 0.35 mg/kg), with 54% of patients experiencing no vomiting and 76% experiencing two or fewer vomiting episodes within the first 24 hours. Overall, ondansetron was well tolerated, and no dose-limiting toxicity was observed. The most common adverse events were mild sedation, mild headache, and transient elevations of transaminases. In a second phase I study, 45 patients receiving cisplatin (median dose 100 mg/m2) were given ondansetron in three IV doses (range, 0.01 mg/kg to 0.48 mg/kg) 4 hours apart. There was no statistically significant difference in antiemetic efficacy among dose levels from 0.06 mg/kg to 0.48 mg/kg; however, there was a trend toward a decrease in the number of patients with failure of antiemetic protection at the higher exposures. Overall, 44% of patients had no emetic episodes, and 81% of patients had two or fewer emetic episodes within the first 24 hours. The number and intensity of adverse events, of which headache was the most common, appeared to increase at the 0.48 mg/kg dose level. A randomized double-blind study that compared three dose levels of ondansetron indicated that three doses of 0.15 mg/kg was superior in efficacy to three doses of 0.015 mg/kg, and not significantly different from three doses of 0.30 mg/kg. Dystonic reactions or akathisia were not noted in any study.