Pharmacokinetics of tirilazad in healthy male subjects at doses above 6 mg/kg/day.

The dose proportionality of tirilazad pharmacokinetics at dosages above 6.0 mg/kg/day were assessed in 18 healthy male volunteers between the ages of 19 and 46 years. Subjects were randomized to receive either 1.5 mg/kg, 3.0 mg/kg, or 4.0 mg/kg tirilazad mesylate every 6 hours for 29 doses (daily doses of 6.0, 12.0, and 16.0 mg/kg/day for 7 days). Each drug dose was administered intravenously over 10 minutes. Plasma tirilazad, U-89678, and U-87999 (active reduced metabolites) were quantified by HPLC. Two subjects in the high dose group withdrew before the end of the study. Following the first dose of tirilazad, dose-corrected pharmacokinetic parameters for all 3 compounds did not differ significantly among dose groups. After the final tirilazad the mean half-life of tirilazad was approximately 80 hours. Mean apparent tirilazad clearance did not differ significantly among groups. Mean U-89678 AUC0-6 following the last tirilazad dose did not differ significantly between the 6.0 and 12.0 mg/kg/day doses, but the value for the 16.0 mg/kg dose was higher than values from both lower doses (p = 0.044 and 0.056, respectively). Similar results were obtained for U-87999. The dose effects observed for the pharmacokinetics of these 2 metabolites may have been a function of intersubject variability. When combined with previous data concerning the dose proportionally of tirilazad pharmacokinetics at doses less than 6.0 mg/kg/day, the data from the present study suggest that the pharmacokinetics of tirilazad are approximately linear over a dosage range of 1.0-16.0 mg/kg/day. Due to the inability to assess the plasma protein binding of tirilazad and its reduced metabolites, the clinical significance of the departure from linearity of the pharmacokinetics of U-89678 and U-87999 cannot be directly assessed. Further study at higher doses will be needed to address this issue.