ate symptomatic treatment instituted immediately.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: immune sera immunoglobulins, specific immunoglobulins; ATC Code: J06BB16.
Palivizumab is a humanised IgG1κ monoclonal antibody directed to an epitope in the A antigenic site of the fusion protein of respiratory syncytial virus (RSV). This humanised monoclonal antibody is composed of human (95%) and murine (5%) antibody sequences. It has potent neutralising and fusion-inhibitory activity against both RSV subtype A and B strains.
Palivizumab serum concentrations of approximately 30 μg/ml have been shown to produce a 99% reduction in pulmonary RSV replication in the cotton rat model.
In vitro studies of antiviral activity
The antiviral activity of palivizumab was assessed in a microneutralization assay in which increasing concentrations of antibody were incubated with RSV prior to addition of the human epithelial cells HEp-2. After incubation for 4-5 days, RSV antigen was measured in an enzyme-linked immunosorbent assay (ELISA). The neutralization titre (50% effective concentration [EC50]) is expressed as the antibody concentration required to reduce detection of RSV antigen by 50% compared with untreated virus-infected cells. Palivizumab exhibited median EC50 values of 0.65 μg/ml (mean [standard deviation] = 0.75 [0.53] μg/ml; n=69, range 0.07–2.89 μg/ml) and 0.28 μg/ml (mean [standard deviation] = 0.35 [0.23] μg/ml; n=35, range 0.03–0.88 μg/ml) against clinical RSV A and RSV B isolates, respectively. The majority of clinical RSV isolates tested (n=96) were collected from subjects in the United States.
Resistance
Palivizumab binds a highly conserved region on the extracellular domain of mature RSV F protein, referred to as antigenic site II or A antigenic site, which encompasses amino acids 262 to 275. In a genotypic analysis of 126 clinical isolates from 123 children who failed immunoprophylaxis, all RSV mutants that exhibited resistance to palivizumab (n=8) were shown to contain amino acid changes in this region of the F protein. No polymorphic or non-polymorphic sequence variations outside of the A antigenic site on the RSV F protein were shown to render RSV resistant to neutralisation by palivizumab. At least one of the palivizumab resistance-associated substitutions, N262D, K272E/Q, or S275F/L was identified in these 8 clinical RSV isolates resulting in a combined resistance-associated mutation frequency of 6.3% in these patients. A review of clinical findings did not reveal an association between A antigenic site sequence changes and RSV disease severity among children receiving palivizumab immunoprophylaxis who develop RSV lower respiratory tract disease. Analysis of 254 clinical RSV isolates collected from immunoprophylaxis-naïve subjects revealed palivizumab resistance-associated substitutions in 2 (1 with N262D and 1 with S275F), resulting in a resistance associated mutation frequency of 0.79%.
Immunogenicity
Antibody to palivizumab was observed in approximately 1% of patients in the IMpact-RSV during the first course of therapy. This was transient, low titre, resolved despite continued use (first and second season), and could not be detected in 55 of 56 infants during the second season (including 2 with titres during the first season). Immunogenicity was not studied in the congenital heart disease study. Antibody to palivi |
