Single-dose pharmacokinetics and safety of HA-1A, a human IgM anti-lipid-A monoclonal antibody, in pediatric patients with sepsis syndrome.
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 per 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.
Department of Pediatrics, Texas Children's Hospital, Houston.
M J
MJ
Romano
G L
GL
Kearns
S L
SL
Kaplan
R F
RF
Jacobs
A
A
Killian
J S
JS
Bradley
M M
MM
Moss
R
R
Van Dyke
W
W
Rodriguez
R C
RC
Straube
D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D001424:Bacterial Infections / Q000628:therapy*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D007223:Infant; D008297:Male; D013577:Syndrome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007075:Immunoglobulin M; C068069:nebacumab