Evaluation of the safety and pharmacokinetic profile of a new, pasteurized, human tetanus immunoglobulin administered as sham, postexposure prophylaxis of tetanus

Abstract

In a monocentric, double-blind, randomized trial, we examined the safety and pharmacokinetic profile of a new, pasteurized, human tetanus immunoglobulin (P-HTIG). As part of the purification process, P-HTIG has undergone a heat treatment step (10 h at 60 degrees C) and the removal of Merthiolate. Forty-eight adults with a history of tetanus vaccination were randomized into four groups (n = 12 per group) to receive one of two different batches of this P-HTIG simultaneously with either tetanus-diphtheria (Td) vaccine (sham, postexposure prophylaxis of tetanus) or placebo. Local reactions at the injection site were followed for the first 3 days after injection, and systemic reactions were followed during the entire study period, i.e., up to 42 days posttreatment. Blood samples for tetanus antibody titer determination (enzyme-linked immunosorbent assay method) were drawn prior to treatment on day 0 and on days 1, 2, 3, 7, 14, 21, 28, 35, and 42. A normalization of tetanus antibody titers (subtraction of the day 0 value for each subject at each time period) was performed to assess the additive effect of P-HTIG on tetanus antibody titers. The pharmacokinetic parameters were determined by both a compartmental analysis (modelization) and a noncompartmental analysis. No severe adverse reactions were reported. The rate of local reactions at the P-HTIG injection site was 27%. All local reactions were mild and resolved within 2 days. In contrast, local reactions at the vaccine injection site were seen in 79% of the subjects. The rate of systemic reactions was similar in the P-HTIG plus Td vaccine group (33%) and in the P-HTIG plus placebo group (21%), and all these reactions were mild. In the P-HTIG plus placebo group, tetanus antibody titers rose to a maximum of 0.313+/-2.49 IU/ml after 4.4 days; in the P-HTIG plus Td vaccine group, a maximum concentration of 15.2+/-2.42 IU/ml was reached 19 days postinjection. In both groups, 100% of the patients had seroprotective levels of tetanus antibodies (> or = 0.01 IU/ml) 2 days following treatment. An anamnestic response to Td vaccine appeared 7 days postimmunization. In conclusion, P-HTIG has a good safety and pharmacokinetic profile. Our results confirm that immunoglobulin should be associated with vaccine in the treatment of tetanus-prone wounds.

Figures

FIG. 1

Evolution of tetanus antibody titers (mean ± SE; log-linear scale) after administration of P-HTIG plus placebo (groups A and B) (▪, n = 24) or P-HTIG plus Td vaccine (groups C and D) (○; n = 24).

FIG. 2

Evolution of tetanus antibody titers (mean ± SE; log-linear scale; data normalized) after administration of P-HTIG plus placebo (groups A and B) (▪; n = 6) or P-HTIG plus Td vaccine (groups C and D) (○; n = 13).

FIG. 3

Calculated tetanus concentration profile (log-linear scale; data normalized) following administration of P-HTIG alone (lower curve) or P-HTIG with Td vaccine (upper curve). Calculated as described in the text with the following values for the parameters: kel = 0.0246, k01 = 15, ka = 8.65, kb = 0.175, tlag = 0.865 days, tlag1 = 0.298 days, and tlag2 = 6.05 days.

FIG. A1

Combined model for groups A and B.

FIG. A2

Combined model for groups C and D.