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 mono clonal antibody with specificity for the lipid A region of endotoxin, were evaluated in a multicenter trial of pediatric patients with sepsi s 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 ph armacokinetic 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) a nd apparent volume of distribution at steady state (0.11 +/- 0.03 L/kg ) were larger than values reported previously in adults with sepsis sy ndrome. Elimination half-life (14.5 +/- 6.8 hours) and plasma concentr ation after infusion (30.7 + 14.5 mg/L) were similar to adults' values . In an additional three patients studied for 72 hours after administr ation, a biexponential function (i.e., two-compartment open model) bes t 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 obser ved in children's blood samples during 36 hours. Within the pediatric population, no age-related differences in pharmacokinetics could be de tected. Drug disposition was unaffected by renal or hepatic dysfunctio n. Decreased blood pressure was the most frequently reported adverse e vent; 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 clo acae was the most common pathogen isolated. Haemophilus influenzae typ e 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 s ide effects. The pharmacokinetic-pharmacodynamic behavior of HA-1A in children requires further study to determine whether developmental dif ferences exist and how these differences might affect drug administrat ion. Efficacy remains to be studied.