Safety, tolerability and pharmacokinetics of escalating doses of NXY-059 in healthy young and elderly subjects.

OBJECTIVE: NXY-059 is a novel, free-radical trapping, neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischaemic stroke. This study evaluated the safety, tolerability and pharmacokinetics of NXY-059 in the unbound steady-state plasma concentration (Cu(ss)) exposure range of 50-300 micromol/L in healthy young and elderly subjects.

RESEARCH DESIGN AND METHODS: The primary objective of this two-centre, randomised, double-blind, placebo-controlled, dose-escalating study was to investigate the safety and tolerability, including renal function parameters and vasoirritative effects, of 8-h and 72-h intravenous infusions of NXY-059 in healthy young (20-45 years) and elderly (55-75 years) male and female subjects. The secondary objective of the study was to evaluate the pharmacokinetics of 8-h and 72-h intravenous infusions of NXY-059 in these subjects, using blood and urine samples taken during and after NXY-059 infusion as well as the doses administered.

RESULTS: Of the 104 healthy volunteers who participated in the study, 72 were young and 32 were elderly. The type and incidence of adverse events in NXY-059 and placebo subjects were similar, although headache was more common in the NXY-059 group. Renal function was not altered in either group. Thrombophlebitis was reported in two elderly subjects: one receiving NXY-059 and one receiving placebo. A proportional relationship between AUC and dose for the 8-h and 72-h infusions was observed, and clearance did not change with dose.

CONCLUSIONS: NXY-059 was well tolerated at all plasma concentrations tested in both the young and elderly subjects, and no safety concerns were raised. Linear pharmacokinetics were observed following 8-h and 72-h infusions of NXY-059 at doses resulting in an average Cu(ss) in the 52-317 micromol/L range.