Multicenter study to determine antibody concentrations and assess the safety of administration of INH-A21, a donor-selected human Staphylococcal immune globulin, in low-birth-weight infants

Abstract

Nosocomial or late-onset sepsis is a common complication among premature infants, with a frequency inversely correlated with birth weight. Increased susceptibility to infection is due in part to an immature humoral (antibody-mediated) immune response. This study investigated the pharmacokinetics (PKs) and safety of a donor-selected specific intravenous immune globulin (IVIG) preparation, INH-A21 (Veronate), for prevention of sepsis in premature infants. Thirty-six infants weighing between 500 and 1,250 g during the first postnatal week were eligible to begin a series of up to four intravenous infusions of 500 or 750 mg/kg of body weight INH-A21. Blood samples were analyzed for antibodies against the Ser-Asp dipeptide repeat G (SdrG) and clumping factor A (ClfA) surface proteins of staphylococci. Sparse sampling and population PK analyses were performed to derive PK parameters. Following administration of the 500- and 750-mg/kg doses, the estimated average steady-state levels of anti-ClfA were 6.1 U/ml and 9.2 U/ml, respectively, and those of anti-SdrG were 5.2 U/ml and 7.7 U/ml, respectively. The elimination half-lives for anti-ClfA and anti-SdrG were 719 h and 701 h, respectively, and the clearances were 0.18 ml/h and 0.21 ml/h, respectively. In the final model, the values of the PK parameters were independent of gestational age. Both doses of INH-A21 were well tolerated, and the safety profile was similar to those of other IVIG preparations. These results suggest that a shorter dosing interval should be utilized between the first and second doses to achieve and maintain higher titers of anti-ClfA and anti-SdrG antibodies. Further studies examining INH-A21 for the prevention of late-onset sepsis in infants within the weight range studied are warranted.

FIG. 1.

ClfA antibody levels for the 500-mg/kg cohort from the final population PK model with 90% confidence interval and actual datum points (solid circles). Due to variability in administration times for doses 2 to 4, samples are displayed based on times relative to the scheduled dose rather than the absolute clock times after the first dose.

FIG. 2.

SdrG antibody levels for the 500-mg/kg cohort from the final population PK model with 90% confidence interval and actual datum points (solid circles). Due to variability in administration times for doses 2 to 4, samples are displayed based on times relative to the scheduled dose rather than absolute clock times after the first dose.

FIG. 3.

ClfA antibody levels for the 750-mg/kg cohort from the final population PK model with 90% confidence interval and actual datum points (solid circles). Due to variability in administration times for doses 2 to 4, samples are displayed based on times relative to the scheduled dose rather than the absolute clock times after the first dose.

FIG. 4.

SdrG antibody levels for the 750-mg/kg cohort from the final population PK model with 90% confidence interval and actual datum points (solid circles). Due to variability in the administration times for doses 2 to 4, samples are displayed based on times relative to the scheduled dose rather than the absolute clock time after the first dose.

FIG. 5.

IgG concentrations from infants in the present study (gray squares, 500-mg/kg group; black diamonds, 750-mg/kg group) compared to the mean ± standard deviation reported by Baker et al. (2) (solid circles), adjusted for dose (to 750 mg/kg). Open triangles, predose concentrations.