Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia

Background. Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants. MEDI-493 (palivizumab) is a humanized monoclonal antibody to the fusion protein of RSV and is active in animal models for prevention of pulmonary RSV replication. Objective. To describe the safety, tolerance, immunogenicity and pharmacokinetics of repeat intravenous doses of MEDI-493 in premature infants or infants with bronchopulmonary dysplasia. Design. Phase I/II multicenter, randomized, double blind, placebo-controlled, dose escalation trial. Patient population. Infants born prematurely (≤35 weeks of gestation) who were ≤6 months of age and infants with bronchopulmonary dysplasia who were ≤24 months of age were eligible for study participation. Study agents. Participants received 3, 10 or 15 mg/kg MEDI-493 or 0.9% saline intravenously every 30 days for up to five doses. Results. MEDI-493 was safe and well-tolerated and did not induce a specific anti-MEDI-493 response. The mean half-life of 20 days was comparable with that of other immunoglobulin G preparations. Mean trough serum concentrations 30 days after infusion 1 were 6.8, 36.1 and 60.6 μg/ml for the 3-, 10- and 15-mg/kg dose groups, respectively. After Infusion 2 the trough concentrations were 11.9, 45.2 and 70.7 μg/ml. After subsequent doses the mean trough values ranged from 14 to 18 μg/ml in those given 3 mg/kg and were >40 μg/ml for patients who received 10 or 15 mg/kg MEDI-493 (46 to 72 μg/ml and 88 to 96 μg/ml, respectively). Conclusions. MEDI-493 was safe and well-tolerated in this high risk pediatric population. Mean serum concentrations of MEDI-493 that have been shown to produce a 2-log reduction in pulmonary RSV titer in cotton rats were maintained when 10 or 15 mg/kg MEDI-493 was given every 30 days to pediatric patients at high risk for serious RSV disease. Monthly doses of 15 mg/kg maintained concentrations of >40 μg/ml for the majority of patients.