Randomized Comparison Study of Novel Recombinant Human Antithrombin Gamma and Plasma-Derived Antithrombin in Healthy Volunteers
Clinical drug investigation(2019)
摘要
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 max,day3 ) and area under the plasma antithrombin activity-time curve after the third dose (AUC 48– t ) 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 max,day3 was 1.67 IU/mL in the rhAT-gamma group and 1.77 IU/mL in the pAT group; mean AUC 48–121 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 max,day3 and AUC 48– t 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 max,day3 and AUC 48– t 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.
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