Population pharmacokinetics of tirilazad: Effects of weight, gender, concomitant phenytoin, and subarachnoid hemorrhage

Purpose. Data collected during phase I and II in the development of tirilaz ad were pooled and analyzed using nonlinear mixed effects models to assess covariates which might affect tirilazad pharmacokinetics. Methods. Four single dose and five multiple dose studies in normal voluntee rs were combined with two multiple dose studies performed in patients with subarachnoid hemorrhage (SAH) to identify factors related to intersubject v ariability in clearance (CL) and central compartment volume (Vc). Data from 253 subjects, which consisted of 7,219 tirilazad concentrations, were anal yzed. The effects of weight, gender, patient versus volunteer status, and p henytoin use were evaluated. Results. Relative to male volunteers not receiving concomitant phenytoin, s ignificant effects on clearance included: a 46% increase in volunteers rece iving phenytoin, and an 82% increase in clearance associated with SAH patie nts (all of whom received phenytoin). significant effects on Ve were: a 26% increase for female volunteers not receiving phenytoin, a 12% decrease for volunteers receiving concomitant phenytoin, a 152% increase for male SAH p atients, and a 270% increase for female SAH patients. Incorporating patient covariate effects substantially reduced the interindividual variability (f rom 27.9% to 24.7% for clearance and from 48.2% to 37.5% for Vc). Residual variability was estimated at 66% coefficient of variation (CV) in SAH patie nts and at 22-48% CV over the range of predicted concentrations in normal v olunteers. Conclusions. The most important factors affecting tirilazad pharmacokinetic s are the administration of phenytoin (increased CL) and SAH (increased Ve and residual variability). The effect of gender on tirilazad pharmacokineti cs was modest.