SAFETY AND PHARMACOKINETICS OF MULTIPLE DOSES OF RECOMBINANT HUMAN CUZN SUPEROXIDE-DISMUTASE ADMINISTERED INTRATRACHEALLY TO PREMATURE NEONATES WITH RESPIRATORY-DISTRESS SYNDROME

Objectives. To examine the safety and pharmacokinetics of multiple int ratracheal (IT) doses of recombinant human CuZn superoxide dismutase ( rhSOD) in premature infants with respiratory distress syndrome who are at risk for developing bronchopulmonary dysplasia (BPD). Methods. Thi rty-three infants (700 to 1300 g) were randomized and blindly received saline, 2.5 mg/kg or 5 mg/kg rhSOD IT within 2 hours of surfactant ad ministration. Infants were treated every 48 hours (as long as endotrac heal intubation was required) up to 7 doses. Serial blood and urine st udies, chest radiographs, neurosonograms, SOD concentration and activi ty measurements, and tracheal aspirate (TA) inflammatory markers were assessed throughout the 28-day study. Results. SOD concentrations in s erum (0.1 [0.05/0.15] mu g/mL-geometric mean with lower/upper confiden ce intervals), tracheal aspirates (TA) (0.2 [0.1/0.3] mu g/mL) and uri ne (0.3 [0.2/0.4] mu g/mL) were similar at baseline in all 3 groups an d did not change significantly in the placebo group. In the rhSOD trea tment groups, SOD concentrations were increased on day 3 and did not c hange significantly thereafter over the 14-day dosing period (also mea sured on days 5, 7, and 13). SOD concentrations averaged 0.4 [0.3/0.5] mu g/mL in serum, 0.8 [0.6/1.2] mu g/mL in TA and 1.1 [1.0/1.3] mu g/ mL in urine for the low-dose group and 0.6 [0.5/0.7] mu g/mL in serum, 1.1 [0.9/1.5] mu g/mL in TA, and 2.2 [1.6/2.9] mu g/mL in urine for t he high-dose group over the 14-day dosing period. Enzyme activity dire ctly correlated with SOD concentration and rhSOD was active even when excreted in urine. TA markers of acute lung injury (neutrophil chemota ctic activity, albumin concentration) were lower in the rhSOD agroups compared with placebo. No significant differences in any clinical outc ome variable were noted between groups. Conclusions. These data indica te that multiple IT doses of rhSOD increase the concentration and acti vity of the enzyme in serum, TA and urine, reduce TA lung injury marke rs and are well-tolerated. Further clinical trials examining the effic acy of rhSOD in the prevention of BPD are warranted.