Pharmacokinetics of Tirilazad and U-89678, an Active, Reduced Metabolite, following Acute Head Trauma in Adults.

Abstract

The pharmacokinetics of tirilazad and U-89678 (an active metabolite) were evaluated in 55 adults (48 males, 7 females) with moderate or severe head injury who received 10.0mg/kg/day tirilazad mesylate for 5days. Trough plasma samples were obtained daily; serial plasma samples were obtained over one dosing interval on day 5. Plasma tirilazad and U-89678 were quantified by HPLC. Sixty-two percent of the subjects received concomitant anticonvulsants, of which 91% received phenytoin. Plasma tirilazad and U-89678 concentrations in head-injured patients were similar to or lower than those observed in healthy volunteers. Sufficient data were available to calculate pharmacokinetic parameters for day 5 in 26 patients; 11 received no anticonvulsants. The AUC0–6 (area under the concentration–time curve at 0–6 h) for tirilazad mesylate on day 5 in patients receiving anticonvulsants (median=4972ng h/mL) differed significantly from that in patients not receiving anticonvulsants (median=9704ng h/mL) (p=0.0051). Similarly, the AUC0–6 of U-89678 in patients receiving anticonvulsants (median=561ng h/mL) was significantly different from that in patients who were not (median=2494ng h/mL) (p=0.0016). Comparison of pharmacokinetic data from patients not receiving anticonvulsants to historical data in healthy volunteers suggests that head injury has little effect on tirilazad pharmacokinetics within 5days of injury. These results suggest that the major factor affecting tirilazad pharmacokinetics in head-injured patients is concomitant use of enzyme-inducing anticonvulsants.