Pharmacokinetics of NXY-059, a nitrone-based free radical trapping agent, in healthy young and elderly subjects.

The tolerability, safety, and pharmacokinetics of NXY-059, a nitrone-based free radical trapping agent under development for the treatment of acute ischemic stroke, were investigated in 2 double-blind, placebo-controlled dose-escalation studies in healthy subjects. In the first study in 6 panels of young male subjects (n = 48, 22-45 years), constant rate infusions lasted 8 hours and ranged from 0.16 to 5.25 micromol/kg/h (0.06 to 2.0 mg/kg/h). In the second study, elderly male and female subjects (n = 24, 57-72 years) were infused over 24 hours or 72 hours to reach target plasma levels of 30 micromol/L or 60 micromol/L, respectively, using doses in the range 1.4-4.0 micromol/kg/h. With a 1-hour loading infusion set at 3 times the maintenance infusion rate, the target plasma level was reached in 1 hour. Adverse events were mild or moderate, and no clinically relevant changes in vital signs, ECG recordings, or laboratory values were noted. Steady-state levels in both studies increased proportionally to the infusion rate, indicating linear kinetics. Renal elimination was predominant, the recovery of unchanged drug in urine being 80% to 90% irrespective of age. The average plasma clearance in young and elderly subjects was 7.0 L/h and 4.1 L/h, respectively. It was estimated that glomerular filtration and active tubular secretion of NXY-059 accounted for approximately two-thirds and one-third of its renal clearance, respectively. In the elderly, clearance of NXY-059 was significantly correlated to creatinine clearance. The renal clearance was insensitive to variations in urine pH and urine flow rate. It appears that NXY-059 is well tolerated and has a highly predictable pharmacokinetic profile.