Randomized Comparison Study of Novel Recombinant Human Antithrombin Gamma and Plasma-Derived Antithrombin in Healthy Volunteers.

BACKGROUND AND OBJECTIVE

This paper describes two studies, which aimed to compare the safety and plasma antithrombin activity of recombinant human antithrombin gamma (rhAT-gamma) with plasma-derived antithrombin (pAT) 60 IU/kg, and to establish bioequivalence by adjusting the rhAT-gamma dose to that at which plasma antithrombin activity equaled that for pAT 60 IU/kg, based on results of the first study.

METHODS

Healthy adult men aged 20-45 years received once-daily doses of rhAT-gamma or pAT intravenously for 3 days (first study: 60 IU/kg of each; second study: 72 IU/kg of rhAT-gamma and 60 IU/kg of pAT). Maximum plasma antithrombin activity after three doses (C) and area under the plasma antithrombin activity-time curve after the third dose (AUC) were analyzed. Safety was also assessed.

RESULTS

In the first study, we compared AUCs to 121 h (when the lower limit of quantification was first observed). Mean C was 1.67 IU/mL in the rhAT-gamma group and 1.77 IU/mL in the pAT group; mean AUC was 58.44 and 71.94 IU·h/mL, respectively. Thus, we set the dose of rhAT-gamma in the second study to 72 IU/kg. As a result, ratios of C and AUC in the rhAT-gamma vs. the pAT group were 105.7% (90% confidence interval 100.3, 111.3) and 100.5% (90% confidence interval 91.5, 110.4), respectively. Adverse events were more frequent in the rhAT-gamma group.

CONCLUSIONS

As 90% confidence intervals for C and AUC ratios for rhAT-gamma:pAT were within the acceptability range for bioequivalence, rhAT-gamma (72 IU/kg) and pAT (60 IU/kg) are considered bioequivalent.