SAFETY AND PHARMACOKINETICS OF RECOMBINANT HUMAN SUPEROXIDE-DISMUTASEADMINISTERED INTRATRACHEALLY TO PREMATURE NEONATES WITH RESPIRATORY-DISTRESS SYNDROME

Objective. As a first step in the evaluation of recombinant human CuZn superoxide dismutase (rhSOD) in the prevention of neonatal lung injur y, safety and pharmacokinetics of intratracheally (IT) administered rh SOD were studied. Methods. Twenty-six preterm infants weighing 750 to 1250 g with respiratory distress syndrome were studied in three sequen tial groups (placebo, 0.5, and 5 mg/kg). Placebo or rhSOD was administ ered IT 30 minutes after the first surfactant dose. Serial blood and u rine studies, rhSOD levels, tracheal aspirate fluid (TAF) markers of a cute inflammation, radiographs, and ultrasounds were performed over th e 28-day study period. Results. Serum SOD concentrations were similar at baseline for all three groups (geometric mean 0.2, upper-lower limi t 0.1 to 0.2 mu g/mL). In the 0.5-mg/kg group, levels were highest at 12 hours (geometric mean 0.7, upper-lower limit 0.5 to 0.8 mu g/mL) an d returned to baseline by day 3. In the 5-mg/kg group, levels were hig hest at 6 hours (geometric mean 3.0, upper-lower limit 2.3 to 4.0 mu g /mL) and returned to baseline by day 4. Concentrations of SOD in TAF w ere also similar at baseline for all. three groups (geometric mean 0.2 , upper-lower limit 0.2 to 0.3 mu g/mL). There were no significant inc reases in the placebo group, but levels in the 0.5-mg/kg group were hi ghest when first sampled at 24 hours (geometric mean 1.1, upper-lower limit 0.8 to 1.4 mu g/mL) and returned to baseline by day 3. In the 5 mg/kg group, levels were also highest when sampled at 24 hours (geomet ric mean 1.4, upper-lower limit 0.9 to 2.1 mu g/mL) and returned to ba seline by day 4. Urine levels were highest at 12 hours in both the 0.5 -mg/kg (geometric mean 1.3, upper-lower limit 1.0 to 1.7 mu g/mL) and 5-mg/kg infants (geometric mean 6.4, upper-lower limit 3.9 to 10.4 mu g/mL) and decreased significantly by days 2 to 3. rhSOD activity assay s (serum, TAF, and urine) demonstrated that the enzyme still possessed significant activity. No adverse effects of rhSOD were found. TAF neu trophil chemotactic activity and albumin concentrations, important acu te lung injury markers, were significantly lower in the high-dose rhSO D group compared with the other groups. Conclusions. Data suggest that a single IT dose of rhSOD results in significant increases in both co ncentration and activity of the antioxidant in serum; TAF, and urine f or 2 to 3 days. The enzyme appears to be well tolerated, and TAF infla mmatory markers are reduced after administration. This has important i mplications in rhSOD trials to prevent acute and chronic lung injury i n preterm neonates.