EVALUATION OF THE PHARMACOKINETICS AND TOLERABILITY OF TIRILAZAD MESYLATE, A 21-AMINOSTEROID FREE-RADICAL SCAVENGER .2. MULTIPLE-DOSE ADMINISTRATION

The multiple dose tolerability and pharmacokinetics of tirilazad mesylate, a 21-aminosteroid free radical scavenger, were assessed in 50 healthy male volunteers. Volunteers were randomized to receive intravenous normal saline placebo (n = 10), citrate vehicle placebo (n = 10), or 0.5 mg/kg/day (n = 6), 1.0 mg/kg/day (n = 6), 2.0 mg/kg/day(n = 6), 4.0 mg/kg/day (n = 6), or 6.0 mg/kg/day (n = 6) tirilazad mesylate in divided doses every 6 hours for 5 days, for a total of 21 doses. Drug was infused over 10 or 30 minutes. All tirilazad mesylate treatment groups and the citrate vehicle group had significantly more frequent and more intense pain at the injection site than did the saline group, but the pain intensity did not require interruption of dosing. Three episodes of clinical thrombophlebitis were observed, No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, or renal function were apparent. Moderate and transient increases in serum alanine transaminase were observed in several subjects. In the 6.0 mg/kg/day group, 50% of the subjects exhibited increased alanine transaminase. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol, eosinophil, or lymphocyte levels). Tirilazad mesylate pharmacokinetics were linear over the dosage range studied. Steady state appeared to be achieved by the fifth day of dosing. After the last dose, a mean terminal half-life of 35 hours was observed. This terminal phase is not observed after single dosing, but the portion of the area under the plasma tirilazad concentration-time curve represented by this terminal phase is estimated to account for less than 5% of the total area after a single dose. Thus, single-dose estimates of clearance may be predictive of clearance on multiple dosing, but volume of distribution estimates are not.