Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia

Xavier Sáez-Llorens, Elizabeth Castaño, Donald Null, Jean Steichen, Pablo J. Sánchez, Octavio Ramilo, Franklin H. Top, Edward Connor

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

Background. Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in infants and children. MEDI-493 (palivizumab, Synagis®) is a humanized monoclonal IgG1 antibody to the fusion protein of RSV, and it is highly active in vitro against RSV A and B strains. Objective. To describe the safety, tolerance, immunogenicity and pharmacokinetics of monthly intramuscular injections of MEDI-493 among premature infants and children with bronchopulmonary dysplasia and to compare these data with information previously obtained with intravenous dosing. Design. A Phase I/II multicenter, open label, escalating dose clinical trial. Patient population and dosing regimen. Children (n = 65) born prematurely at ≤35 weeks of gestation who were ≤6 months of age (n = 41) and children with bronchopulmonary dysplasia who were ≤24 months of age (n = 24) were enrolled. From 1 to 5 monthly injections were given at doses of 5 mg/kg (n = 11), 10 mg/kg (n = 6) and 15 mg/kg (n = 48). Serum was collected before administration of each dose, 30 days after the last dose, and 2, 7 and 14 days after the first and second doses for measurement of MEDI-493 concentrations by enzyme-linked immunosorbent assay. Results. The pharmacokinetics of MEDI-493 were similar to those of other human IgG1 antibodies. Mean serum MEDI-493 concentrations were 91.1 μg/ml (range, 52.3 to 174.0) 2 days after the initial dose of 15 mg/kg and 49.2 μg/ml (range, 13.5 to 132.0) at 30 days. Monthly dosing of 15 mg/kg maintained mean trough concentrations of ~70 μg/ml. These concentrations were similar to previously published trough concentrations after iv administration. MEDI-493 injections were well-tolerated. Only three children had adverse events judged to be possibly related to MEDI-493. Ten children had transient, low titer anti-MEDI-493 binding titers (1:10 to 1:40) which were not associated with a pattern of specific adverse events or alterations of MEDI-493 concentrations. Two patients in the 5-mg/kg dose group were hospitalized for RSV; no RSV hospitalizations were found in the higher dose groups. Conclusions. MEDI-493 was safe and well-tolerated. Monthly intramuscular doses of 15 mg/kg maintained mean trough serum concentrations that were above 40 μg/ml (the value associated with 99% reduction of pulmonary RSV in the cotton rat model). These concentrations were similar to those previously reported with iv administration of MEDI-493.

Original languageEnglish (US)
Pages (from-to)787-791
Number of pages5
JournalPediatric Infectious Disease Journal
Volume17
Issue number9
DOIs
StatePublished - Sep 1 1998
Externally publishedYes

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Antibodies, Monoclonal, Humanized
Bronchopulmonary Dysplasia
Respiratory Syncytial Viruses
Premature Infants
Pharmacokinetics
Safety
Palivizumab
Immunoglobulin G
Serum
Sigmodontinae
Injections
Intramuscular Injections

Keywords

  • MEDI-493
  • Monoclonal antibody
  • Palivizumab
  • Respiratory syncytial virus

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Microbiology (medical)

Cite this

Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. / Sáez-Llorens, Xavier; Castaño, Elizabeth; Null, Donald; Steichen, Jean; Sánchez, Pablo J.; Ramilo, Octavio; Top, Franklin H.; Connor, Edward.

In: Pediatric Infectious Disease Journal, Vol. 17, No. 9, 01.09.1998, p. 787-791.

Research output: Contribution to journalArticle

Sáez-Llorens, Xavier ; Castaño, Elizabeth ; Null, Donald ; Steichen, Jean ; Sánchez, Pablo J. ; Ramilo, Octavio ; Top, Franklin H. ; Connor, Edward. / Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. In: Pediatric Infectious Disease Journal. 1998 ; Vol. 17, No. 9. pp. 787-791.
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title = "Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia",
abstract = "Background. Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in infants and children. MEDI-493 (palivizumab, Synagis{\circledR}) is a humanized monoclonal IgG1 antibody to the fusion protein of RSV, and it is highly active in vitro against RSV A and B strains. Objective. To describe the safety, tolerance, immunogenicity and pharmacokinetics of monthly intramuscular injections of MEDI-493 among premature infants and children with bronchopulmonary dysplasia and to compare these data with information previously obtained with intravenous dosing. Design. A Phase I/II multicenter, open label, escalating dose clinical trial. Patient population and dosing regimen. Children (n = 65) born prematurely at ≤35 weeks of gestation who were ≤6 months of age (n = 41) and children with bronchopulmonary dysplasia who were ≤24 months of age (n = 24) were enrolled. From 1 to 5 monthly injections were given at doses of 5 mg/kg (n = 11), 10 mg/kg (n = 6) and 15 mg/kg (n = 48). Serum was collected before administration of each dose, 30 days after the last dose, and 2, 7 and 14 days after the first and second doses for measurement of MEDI-493 concentrations by enzyme-linked immunosorbent assay. Results. The pharmacokinetics of MEDI-493 were similar to those of other human IgG1 antibodies. Mean serum MEDI-493 concentrations were 91.1 μg/ml (range, 52.3 to 174.0) 2 days after the initial dose of 15 mg/kg and 49.2 μg/ml (range, 13.5 to 132.0) at 30 days. Monthly dosing of 15 mg/kg maintained mean trough concentrations of ~70 μg/ml. These concentrations were similar to previously published trough concentrations after iv administration. MEDI-493 injections were well-tolerated. Only three children had adverse events judged to be possibly related to MEDI-493. Ten children had transient, low titer anti-MEDI-493 binding titers (1:10 to 1:40) which were not associated with a pattern of specific adverse events or alterations of MEDI-493 concentrations. Two patients in the 5-mg/kg dose group were hospitalized for RSV; no RSV hospitalizations were found in the higher dose groups. Conclusions. MEDI-493 was safe and well-tolerated. Monthly intramuscular doses of 15 mg/kg maintained mean trough serum concentrations that were above 40 μg/ml (the value associated with 99{\%} reduction of pulmonary RSV in the cotton rat model). These concentrations were similar to those previously reported with iv administration of MEDI-493.",
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T1 - Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia

AU - Sáez-Llorens, Xavier

AU - Castaño, Elizabeth

AU - Null, Donald

AU - Steichen, Jean

AU - Sánchez, Pablo J.

AU - Ramilo, Octavio

AU - Top, Franklin H.

AU - Connor, Edward

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N2 - Background. Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in infants and children. MEDI-493 (palivizumab, Synagis®) is a humanized monoclonal IgG1 antibody to the fusion protein of RSV, and it is highly active in vitro against RSV A and B strains. Objective. To describe the safety, tolerance, immunogenicity and pharmacokinetics of monthly intramuscular injections of MEDI-493 among premature infants and children with bronchopulmonary dysplasia and to compare these data with information previously obtained with intravenous dosing. Design. A Phase I/II multicenter, open label, escalating dose clinical trial. Patient population and dosing regimen. Children (n = 65) born prematurely at ≤35 weeks of gestation who were ≤6 months of age (n = 41) and children with bronchopulmonary dysplasia who were ≤24 months of age (n = 24) were enrolled. From 1 to 5 monthly injections were given at doses of 5 mg/kg (n = 11), 10 mg/kg (n = 6) and 15 mg/kg (n = 48). Serum was collected before administration of each dose, 30 days after the last dose, and 2, 7 and 14 days after the first and second doses for measurement of MEDI-493 concentrations by enzyme-linked immunosorbent assay. Results. The pharmacokinetics of MEDI-493 were similar to those of other human IgG1 antibodies. Mean serum MEDI-493 concentrations were 91.1 μg/ml (range, 52.3 to 174.0) 2 days after the initial dose of 15 mg/kg and 49.2 μg/ml (range, 13.5 to 132.0) at 30 days. Monthly dosing of 15 mg/kg maintained mean trough concentrations of ~70 μg/ml. These concentrations were similar to previously published trough concentrations after iv administration. MEDI-493 injections were well-tolerated. Only three children had adverse events judged to be possibly related to MEDI-493. Ten children had transient, low titer anti-MEDI-493 binding titers (1:10 to 1:40) which were not associated with a pattern of specific adverse events or alterations of MEDI-493 concentrations. Two patients in the 5-mg/kg dose group were hospitalized for RSV; no RSV hospitalizations were found in the higher dose groups. Conclusions. MEDI-493 was safe and well-tolerated. Monthly intramuscular doses of 15 mg/kg maintained mean trough serum concentrations that were above 40 μg/ml (the value associated with 99% reduction of pulmonary RSV in the cotton rat model). These concentrations were similar to those previously reported with iv administration of MEDI-493.

AB - Background. Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in infants and children. MEDI-493 (palivizumab, Synagis®) is a humanized monoclonal IgG1 antibody to the fusion protein of RSV, and it is highly active in vitro against RSV A and B strains. Objective. To describe the safety, tolerance, immunogenicity and pharmacokinetics of monthly intramuscular injections of MEDI-493 among premature infants and children with bronchopulmonary dysplasia and to compare these data with information previously obtained with intravenous dosing. Design. A Phase I/II multicenter, open label, escalating dose clinical trial. Patient population and dosing regimen. Children (n = 65) born prematurely at ≤35 weeks of gestation who were ≤6 months of age (n = 41) and children with bronchopulmonary dysplasia who were ≤24 months of age (n = 24) were enrolled. From 1 to 5 monthly injections were given at doses of 5 mg/kg (n = 11), 10 mg/kg (n = 6) and 15 mg/kg (n = 48). Serum was collected before administration of each dose, 30 days after the last dose, and 2, 7 and 14 days after the first and second doses for measurement of MEDI-493 concentrations by enzyme-linked immunosorbent assay. Results. The pharmacokinetics of MEDI-493 were similar to those of other human IgG1 antibodies. Mean serum MEDI-493 concentrations were 91.1 μg/ml (range, 52.3 to 174.0) 2 days after the initial dose of 15 mg/kg and 49.2 μg/ml (range, 13.5 to 132.0) at 30 days. Monthly dosing of 15 mg/kg maintained mean trough concentrations of ~70 μg/ml. These concentrations were similar to previously published trough concentrations after iv administration. MEDI-493 injections were well-tolerated. Only three children had adverse events judged to be possibly related to MEDI-493. Ten children had transient, low titer anti-MEDI-493 binding titers (1:10 to 1:40) which were not associated with a pattern of specific adverse events or alterations of MEDI-493 concentrations. Two patients in the 5-mg/kg dose group were hospitalized for RSV; no RSV hospitalizations were found in the higher dose groups. Conclusions. MEDI-493 was safe and well-tolerated. Monthly intramuscular doses of 15 mg/kg maintained mean trough serum concentrations that were above 40 μg/ml (the value associated with 99% reduction of pulmonary RSV in the cotton rat model). These concentrations were similar to those previously reported with iv administration of MEDI-493.

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KW - Monoclonal antibody

KW - Palivizumab

KW - Respiratory syncytial virus

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