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

ABSTRACT

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 (Cuss) exposure range of 50-300 μmol/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 µmol/L range.

Key words: :

• Acute ischaemic stroke
• Dose escalating
• Neuroprotectant
• NXY-059
• Pharmacokinetics
• Safety

Notes

* Results from this study were presented in part as a poster at the European Stroke Conference, Lisbon, Portugal, 16-19 May 2001