PHARMACOKINETICS OF TIRILAZAD IN HEALTHY MALE-SUBJECTS AT DOSES ABOVE6 MG KG/DAY/

The dose proportionality of tirilazad pharmacokinetics at dosages abov e 6.0 mg/kg/day were assessed in 18 healthy male volunteers between th e 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 fo r 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 quan tified by HPLC. Two subjects in the high dose group withdrew before th e end of the study. Following the first dose of tirilazad, dose-correc ted pharmacokinetic parameters for all 3 compounds did not differ sign ificantly among dose groups. After the final tirilazad dose the mean h alf-life of tirilazad was approximately 80 hours. Mean apparent tirila zad clearance did not differ significantly among groups. Mean U-89678 AUC(0.6) following the last tirilazad dose did not differ significantl y 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 an d 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 w ith previous data concerning the dose proportionality of tirilazad pha rmacokinetics at doses less than 6.0 mg/kg/day, the data from the pres ent study suggest that the pharmacokinetics of tirilazad are approxima tely linear over a dosage range of 1.0 - 16.0 mg/kg/day. Due to the in ability to assess the plasma protein binding of tirilazad and its redu ced metabolites, the clinical significance of the departure from linea rity of the pharmacokinetics of U-89678 and U-87999 cannot be directly assessed. Further study at higher doses will be needed to address thi s issue.