Multiple-dose tolerability and pharmacokinetics of tirilazad mesylate at doses of up to 10 mg/kg/day administered over 5-10 days in healthy volunteers.

Multiple dose pharmacokinetics and tolerability of tirilazad mesylate were assessed at the maximum dosage and duration expected for tirilazad mesylate therapy of subarachnoid hemorrhage and head injury. Healthy male subjects (47) received either 1 mg/kg/day, 3 mg/kg/day, 6 mg/kg/day, or 10 mg/kg/day tirilazad mesylate, given as 10 minute i.v. infusions every 6 hours for 21 (at the highest dose) or 41 doses. Plasma tirilazad mesylate and U-89678, an active metabolite, were quantified by HPLC. Thirty-nine subjects completed the study. Tirilazad mesylate was generally well tolerated; injection site irritation was the primary adverse effect. Sporadic, dose unrelated elevations in liver enzymes were observed. All medical events were reversible. No clinically significant effects on vital signs, cardiac telemetry, or other laboratory values were seen. Both tirilazad and U-89678 accumulated on multiple dosing, and steady-state plasma levels were approximated by day 11 of dosing. U-89678 average steady-state concentrations approached 58% of those of the parent compound in the 6.0 mg/kg/day dose group. Following the last dose, mean half-lives for tirilazad ranged from 61.2-123 hours; mean U-89678 half-lives ranged from 60.5-111 hours. Tirilazad mesylate pharmacokinetics exhibited slight nonlinearity, AUC0-6 values for the 6 mg/kg/day were 33% higher than those predicted based on data from the 1.0 mg/kg dose group. Neither the long half-lives of U-89678 and tirilazad nor slight nonlinearity of tirilazad pharmacokinetics are likely to have significant clinical impact during short-term treatment of acute neurological injury.