Single-dose pharmacokinetics and safety of HA-1A, a human IgM anti-lipid-A monoclonal antibody, in pediatric patients with sepsis syndrome

Michael J. Romano, Gregory L. Kearns, Sheldon L. Kaplan, Richard F. Jacobs, Anthony Killian, John S. Bradley, M. Michele Moss, Russell Van Dyke, William Rodriguez, Richard C. Straube

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The pharmacokinetics and safety of HA-1A (Nebacumab), a human IgM monoclonal antibody with specificity for the lipid A region of endotoxin, were evaluated in a multicenter trial of pediatric patients with sepsis syndrome or septic shock. Forty-two patients received a total of 44 infusions of drug, at a dose of 3 mg/kg (maximum 100 mg). The mean age was 7 years 10 months (range, 11 months to 16 years 7 months). The pharmacokinetic behavior of HA-1A during 36 hours was best described by a one-compartment open model. Clearance (6.1 ± 2.0 ml/kg per hour) and apparent volume of distribution at steady state (0.11 ± 0.03 L/kg) were larger than values reported previously in adults with sepsis syndrome. Elimination half-life (14.5 ± 6.8 hours) and plasma concentration after infusion (30.7 ± 14.5 mg/L) were similar to adults' values. In an additional three patients studied for 72 hours after administration, a biexponential function (i.e., two-compartment open model) best described the pharmacokinetic behavior of HA-1A: clearance (1.5 ± 1.4 ml/hr peak kilogram) and apparent volume of distribution at steady state (0.2 ± 0.02 L/kg) were different (p < 0.002) from values observed in children's blood samples during 36 hours. Within the pediatric population, no age-related differences in pharmacokinetics could be detected. Drug disposition was unaffected by renal or hepatic dysfunction. Decreased blood pressure was the most frequently reported adverse event; 4 (9%) episodes in 44 infusions were considered possibly related to the study drug. Gram-negative bacteremia was documented in 23 (55%) of 42 patients. The overall mortality rate was 31%. Enterobacter cloacae was the most common pathogen isolated. Haemophilus influenzae type b was isolated from one child with sepsis syndrome. We conclude that infusion of HA-1A in children is associated with a low incidence of side effects. The pharmacokinetic-pharmacodynamic behavior of HA-1A in children requires further study to determine whether developmental differences exist and how these differences might affect drug administration. Efficacy remains to be studied.

Original languageEnglish (US)
Pages (from-to)974-981
Number of pages8
JournalJournal of Pediatrics
Volume122
Issue number6
DOIs
StatePublished - 1993

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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