Safety and pharmacokinetics of an intramuscular monoclonal antibody (SB209763) against respiratory syncytial virus (RSV) in infants and young children at risk for severe RSV disease

We conducted a multicenter, double-blind, placebo-controlled, randomized tr ial of a humanized monoclonal antibody against a respiratory syncytial viru s (RSV) fusion protein (SE 209763) to evaluate its safety, pharmacokinetics , and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (less than or equal to 35 weeks' gestatio n) or exhibited bronchopulmonary dysplasia were administered either single or repeat (two doses, 8 weeks apart) intramuscular injections of SE 209763 at a concentration of 0.25, 1.25, 5.0, or 10.0 mg/kg or of a placebo. Four of 229 adverse events were considered related to the study drug, including purpura (n = 3) and thrombocytosis (n = 1). No subject developed a detectab le level of anti-SE 209763 antibody. Approximately 1 week after administrat ion of the second dose of SE 209763 at 10 mg/kg, the mean plasma concentrat ion (n = 9) was 68.5 mu g/ml. The terminal half-life (T-1/2) determined by noncompartmental analysis ranged from 22 to 50 days. The population pharmac okinetics for SE 209763 following intramuscular administration was appropri ately described by a one-compartment model with first-order input and elimi nation. Higher values for clearance and volume of distribution at steady st ate were observed for younger patients, with values decreasing to 0.143 (ml /h)/kg and 161 mL/kg, respectively, by a mean age of 298 days (similar to 1 0 months). The mean T-1/2 of SE 209763 for the study population was 32.5 da ys. No other factor (dose, weight, gender, race, premature birth, or bronch opulmonary dysplasia) was observed to alter the population pharmacokinetics of SE 209763 in this study of infants and young children. The mean neutral ization titer on day 6 was 286, and the mean fusion inhibition titer was 36 . At least 57% of subjects dosed at 1.25 to 10.0 mg of SE 209763 per kg of body weight who were seronegative at baseline experienced a fourfold or gre ater increase in fusion inhibition titer. Nine RSV infections were document ed during the 16-week course of the study; the numbers of RSV infections we re similar for the different regimens, including the placebo. The doses of SE 209763 studied may have been insufficient to confer protection against R SV lower respiratory tract disease; these results suggest that additional t rials using higher doses of monoclonal antibody for immunoprophylaxis shoul d be considered.