EVALUATION OF THE PHARMACOKINETICS AND TOLERABILITY OF TIRILAZAD MESYLATE, A 21-AMINOSTEROID FREE-RADICAL SCAVENGER .1. SINGLE-DOSE ADMINISTRATION

The single-dose tolerability and pharmacokinetics of tirilazad mesylate, a 21-aminosteroid free radical scavenger, were assessed in 47 healthy male subjects. Subjects were randomized to receive citrate vehicle (n = 12) or 0.25 mg/kg (n = 9), 0.5 mg/kg (n = 9), 1.0 mg/kg (n = 8), or 2.0 mg/kg (n = 9) tirilazad mesylate by 0.5-hour intravenous infusion. Injection site pain was observed with approximately equal frequency in both vehicle and tirilazad mesylate treatment groups. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, liver enzymes, or renal function were apparent. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol, eosinophil, or lymphocyte levels). Maximal plasma concentrations of tirilazad mesylate increased linearly with dose. Limited assay sensitivity at the lower two doses prevented determination of the dose proportionality of tirilazad area under the curve. The apparent elimination half-life at the higher doses was 3.7 hours. Clearance of tirilazad mesylate approached liver blood flow. Results indicate that intravenous infusions at these doses are well tolerated and devoid of glucocorticoid effects. Tirilazad mesylate appears to be efficiently cleared by the liver, and its pharmacokinetics are apparently linear over the dosage range studied.