Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke

Background and Purpose-Increased free radical formation contributes to the damage caused to the brain by acute ischemia. NXY-059 is a nitrone-based fr ee radical trapping agent in development for acute stroke. NXY-059 has neur oprotective efficacy when given 5 hours after onset of transient focal isch emia in the rat. Methods-This was a randomized, double-blind, placebo-controlled, parallel g roup, multicenter study that evaluated the safety and tolerability of 2 NXY -059 dosing regimens compared with placebo within 24 hours of acute stroke. NXY-059 was administered as either 250 mg over 1 hour followed by 85 mg/h for 71 hours or 500 mg over 1 hour followed by 170 mg/h for 71 hours; plasm a concentrations were monitored. Neurological and functional outcomes were recorded up to 30 days. Results-One hundred Fifty patients were recruited, of whom 147 received stu dy treatments and completed assessments (50 placebo, 48 lower-dose NXY-059, 49 higher-dose NXY-059). Mean (+/-SD) age was 68 (+/-10) years, and baseli ne National institutes of Health Stroke Scale score was 7.9 (+/-6.2). Serio us adverse events occurred in 16%, 23%, and 16% of patients, respectively, with deaths in 0%, 10%, and 4%, largely following the proportions with prim ary intracerebral hemorrhage (6%, 16%, and 8%). Hyperglycemia, headache, an d fever were common but not related to treatment. The mean unbound steady s tate NXY-059 plasma concentrations were 25 and 45 mu mol/L, respectively. P opulation pharmacokinetic analysis estimated clearance to be 4.6 L/h. Conclusions-NXY-059 was well tolerated in patients with an acute stroke. Th e testing of higher doses in future trials may be justified.