Pharmacokinetics of 8-Hour Intravenous Infusion of NXY-059: A Phase I, Randomized, Double-Blind (Within Dose Panels), Placebo-Controlled Study in Healthy Chinese Volunteers

Background: NXY-059 is a free radical-trapping neuroprotectant that has been reported to reduce infarct size and preserve brain function in experimental models of acute ischemic stroke. NXY-059 administered as an 8- or 72-hour IV infusion has been reported to be well tolerated in healthy young (age, 20-45 years) and older (55-75 years) white volunteers. NXY-059 is no longer in development following a lack of efficacy found in a Phase III trial in patients with acute ischemic stroke. Objectives: The primary objectives of this study were to determine the pharmacokinetic (PK) properties of an 8-hour IV infusion of NXY-059 in healthy Chinese volunteers and to compare those data with those previously reported in the white population, therefore exploring any differences in PK properties between the 2 ethnic groups. Secondary objectives were to evaluate PK linearity and tolerability. Methods: This Phase I, randomized, double-blind (within dose panels), placebo-controlled study was conducted at Peking Union Medical College Hospital, Beijing, China. Healthy male and female Chinese volunteers aged 20 to 45 years were recruited. NXY-059 was administered as a continuous 8-hour IV Infusion, starting with a 1-hour loading dose (dosing rate, 3 x maintenance infusion rare) followed by a 7-hour maintenance dose infusion. Subjects were randomly assigned, in a 3:1 ratio, to receive doses calculated (based on creatinine clearance in individual subjects) to achieve I of 3 concentration targets, or inactive vehicle (sodium chloride; placebo). The target unbound plasma NXY-059 concentrations during constant rate infusion (steady state) (Cu-ss) in the 3 dose panels were 100, 200, and 300 mu mol/L. An explorative bridging analysis was used to compare PK data from this study with those previously reported in the white population. Linearity of NXY-059 PK properties was assessed. Tolerability was assessed using adverse events (spontaneous reporting, study staff observation, and open questioning), physical examination, including vital sign measurement; and electrocardiography and laboratory analysis. Results: Thirty-six subjects were randomized (mean age, 32 years [range, 20-41 years], mean body mass index, 22.6 kg/m(2) [range, 20-26 kg/m(2)]). The target exposures of NXY-059 were achieved (mean [SD] Cu-ss values, 98.3 [8.9], 202.1 [18.3], and 287.9 [25.4] mu mol/L, respectively). Steady-state concentrations appeared to have been reached after 4 hours. From the bridging analysis, comparison of PK properties in the 27 Chinese volunteers versus those in 28 white volunteers found similar total plasma clearance of NXY-059 (estimated Chinese:white clearance ratio, 1.077 [95% CI, 1.009-1.150]). There were no apparent differences in other PK parameters between the 2 ethnic groups. The PK properties of NXY-059 in Chinese volunteers were suggestive of linearity. A total of 7 adverse events were reported, all of mild intensity, in the NXY-059 and placebo groups (thirst and polyuria [each in 2 subjects who received NXY-059 and 1 subject who received placebo]; urinary tract infection [1 subject who received NXY-059]). Conclusions: The results from the present study suggest that the PK properties of NXY-059 were similar in the Chinese and historical white healthy volunteer populations. (Clin Ther. 2008;30:2342-2353) (C) 2008 Excerpta Medica Inc.