MULTIPLE-DOSE TOLERABILITY AND PHARMACOKINETICS OF TIRILAZAD MESYLATEAT 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 tirilaza d 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. infus ions every 6 hours for 21 (at the highest dose) or 41 doses. Plasma ti rilazad mesylate and U-89678, an active metabolite, were quantified by HPLC. Thirty-nine subjects completed the study. Tirilazad mesylate wa s generally well tolerated; injection site irritation was the primary adverse effect. Sporadic, dose unrelated elevations in liver enzymes w ere observed. All medical events were reversible. No clinically signif icant effects on vital signs, cardiac telemetry, or other laboratory v alues were seen. Both tirilazad and U-89678 accumulated on multiple do sing, and steady-state plasma levels were approximated by day 11 of do sing. U-89678 average steady-state concentrations approached 58% of th ose 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 hour s; mean U-89678 half-lives ranged from 60.5-111 hours. Tirilazad mesyl ate pharmacokinetics exhibited slight nonlinearity, AUC0-6 values for the 6 mg/kg/day were 33% higher than those predicted based on data fro m the 1.0 mg/kg dose group. Neither the long half-lives of U-89678 and tirilazad nor slight nonlinearity of tirilazad pharmacokinetics are l ikely to have significant clinical impact during short-term treatment of acute neurological injury.