PEDIATRICS Vol. 97 No. 6 June 1996, pp. 811-817
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Safety and Pharmacokinetics of Recombinant Human Superoxide Dismutase Administered Intratracheally to Premature Neonates With Respiratory Distress Syndrome

Warren N. Rosenfeld MD1, Jonathan M. Davis MD1, Lance Parton MD1, Susan E. Richter MPA1, Anita Price MD2, Edith Flaster MS1, and Nadim Kassem MD3

1 Department of Pediatrics (Neonatology) Winthrop-University Hospital, SUNY Stony Brook School of Medicine, Mineola and Stony Brook, New York
2 Department of Radiology and the CardioPulmonary Research Institute, Winthrop-University Hospital, SUNY Stony Brook School of Medicine, Mineola and Stony Brook, New York
3 Department of Bio-Technology General Corporation, Iselin, New Jersey

Objective. As a first step in the evaluation of recombinant human CuZn superoxide dismutase (rhSOD) in the prevention of neonatal lung injury, safety and pharmacokinetics of intratracheally (IT) administered rhSOD were studied.

Methods. Twenty-six preterm infants weighing 750 to 1250 g with respiratory distress syndrome were studied in three sequential groups (placebo, 0.5, and 5 mg/kg). Placebo or rhSOD was administered IT 30 minutes after the first surfactant dose. Serial blood and urine studies, rhSOD levels, tracheal aspirate fluid (TAF) markers of acute inflammation, radiographs, and ultrasounds were performed over the 28-day study period.

Results. Serum SOD concentrations were similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.1 to 0.2 µg/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, µg/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were highest at 6 hours (geometric mean 3.0, upper-lower limit 2.3 to 4.0 µg/mL) and returned to baseline by day 4. Concentrations of SOD in TAF were also similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.2 to 0.3 µg/mL). There were no significant increases in the placebo group, but levels in the 0.5-mg/kg group were highest when first sampled at 24 hours (geometric mean 1.1, upper-lower limit 0.8 to 1.4 µg/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were also highest when sampled at 24 hours (geometric mean 1.4, upper-lower limit 0.9 to 2.1 µg/mL) and returned to baseline 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 µg/mL) and 5-mg/kg infants (geometric mean 6.4, upper-lower limit 3.9 to 10.4 µg/mL) and decreased significantly by days 2 to 3. rhSOD activity assays (serum, TAF, and urine) demonstrated that the enzyme still possessed significant activity. No adverse effects of rhSOD were found. TAF neutrophil chemotactic activity and albumin concentrations, important acute lung injury markers, were significantly lower in the high-dose rhSOD group compared with the other groups.

Conclusions. Data suggest that a single IT dose of rhSOD results in significant increases in both concentration and activity of the antioxidant in serum, TAF, and urine for 2 to 3 days. The enzyme appears to be well tolerated, and TAF inflammatory markers are reduced after administration. This has important implications in rhSOD trials to prevent acute and chronic lung injury in preterm neonates.

Submitted on February 21, 1995
Accepted on July 10, 1995




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