EFFECT OF INFUSION RATE ON THE PHARMACOKINETICS AND TOLERANCE OF INTRAVENOUS DOLASETRON MESYLATE

OBJECTIVE: TO evaluate the safety, tolerance, and pharmacokinetics of dolasetron mesylate and its active metabolite hydrodolasetron when dol asetron mesylate was administered intravenously at increasing infusion rates. DESIGN: A double-blind, placebo-controlled, parallel-group stu dy. METHODS: Forty-nine healthy nonsmoking male volunteers were random ly assigned to receive intravenous doses of dolasetron mesylate 100 mg or placebo, Three groups of 16 subjects each (12 dolasetron mesylate, 4 placebo) received escalating infusion rates (50, 100, then 200 mg/m in), Physical examinations, vital signs, laboratory tests, and adverse events were recorded before and after administration of the study dru g. Serial blood samples and 12-lead electrocardiogram measurements wer e obtained for 24 hours after the infusion. Plasma samples were analyz ed for dolasetron and hydrodolasetron. RESULTS: Dolasetron mesylate wa s well tolerated, with no apparent differences in vital signs or adver se event profiles among the different rates of infusion, In general, t he pharmacokinetics of dolasetron and hydrodolasetron were superimposa ble among the three infusion rate groups. Plasma dolasetron concentrat ions declined rapidly in all three infusion rate groups, with mean eli mination half-life (t(1/2)) of less than 10 minutes, The reduced metab olite hydrodolasetron, which accounts for most pharmacologic activity, formed rapidly, with maximum concentrations occurring between 0.4 and 0.5 hours and disappeared with a mean t(1/2) of 8-9 hours, The correl ation coefficients of least-squares regression analysis between the ph armacokinetic parameters and the infusion rate of dolasetron were less than 0.083 and the slopes were not significantly different from 0, su ggesting that none of the hydrodolasetron pharmacokinetic parameters w ere affected by rate of infusion.